Category Archives: 6. ART 2011

6.11. Monitoring

– Christian Hoffmann, Christian Noah –

Which parameters should be included in routine laboratory monitoring of HIV-positive patients? What results can be expected? This section deals with viral load, CD4 T cells, routine checks, and plasma levels. Resistance and tropism tests are the subject of a separate chapter (see HIV Resistance Testing). For the tests to be performed on initial presentation see The New Patient.

Viral Load

Viral load is the amount of HIV RNA in the blood. Alongside the CD4 T cell count, viral load has become the most important surrogate marker for HIV infection (Hughes 1997, Mellors 1997, Lyles 2000, Ghani 2001, Phillips 2004). It provides information on how high the risk is for disease progression and whether antiretroviral therapy is indicated; it is the critical value in determining the success of therapy. Viral load assays measure the amount of HIV RNA (viral genetic material), which correlates directly with the number of virions. The units are viral copies/ml (or genome equivalents). This is reported either as a direct whole number or as a logarithmic number. A change of one or more logs refers to the change in viral load by one or more decimal powers. Many labs provide both values, the number and the log. There is no standardized international unit/ml as in used in hepatitis B or C.

Number of copies Log10
10 1.0
50 1.7
100 2.0
500 2.7
1000 3.0
10,000 4.0
50,000 4.7
100,000 5.0
1,000,000 6.0


The higher the viral load, the higher the risk of decrease in CD4 T cells, with subsequent disease progression or occurrence of AIDS-related illnesses (Mellors 1997, Lyles 2000, Phillips 2004). A viral load above 100,000 copies/ml (sometimes even above 50,000 copies/ml) is considered to be high; a value below 10,000 copies/ml (sometimes below 5000 copies/ml), low. However, these thresholds are not absolute and only provide points of reference.

The effects of plasma viremia on immune status can vary greatly between individuals. There are some patients whose CD4 T cells remain stable for relatively long periods despite having a high viral load, while others experience a rapid drop, although the viral load is relatively low. Even in the so-called elite controllers in which the viral load is undetectable without ART a slow but constant drop in the CD4 cells can be observed (Stellbrink 2008).

Viral load is probably lower in women than in men. In a meta-analysis, the difference was 41% or 0.23 logs (95% CI 0.16-0.31 logs) (Napravnik 2002). The reason for this phenomenon remains unclear and whether it should have an impact on the indication for treatment is still the subject of debate.


Three methods or assays are currently used to measure viral load: Reverse Transcription-Polymerase Chain Reaction (RT-PCR); branched-chain DNA (bDNA); and, occasionally, Nucleic Acid Sequence-Based Amplification (NASBA). These three methods differ both in levels of detection and in the linear range within which measurement is reliable or reproducible (see Table 11.1). In the case of PCR and NASBA, the viral RNA is transformed in several enzymatic steps and then amplified to measurable amounts. Detection occurs after binding of marked DNA fragments. bDNA does not require an enzymatic step; signal amplification occurs via binding of branched DNA fragments to viral RNA.

The market for assay systems is very dynamic. New assay systems will become available, existing ones further developed. Siemens, for example, offers an RT-PCR in addition to bDNA technology. Roche concentrates on RT-PCR and is working on additional functions such as “dual-target detection” for more successful results. This means that not one section of the viral RNA, like before, but two sections can be duplicated at the same time. If duplication fails in one section on account of the high variability of the HIV genome (the result in this case would be incorrect negative), it will be duplicated in the second section. Besides already established manufacturers, newer companies such as Qiagen are trying to gain market share. Experience will show whether their testing systems are reliable or not.

Recent further developments also concern a reduction below detection level which is at 20 copies/ml in the most sensitive tests. Clinical relevance of a viral load below 50 copies/ml is questionable due to lack of data. It should be noted that a higher sensitivity can lead to insecurity in patients and clinicians and to more frequent control tests.

Although intra-assay variability is fairly good for all three methods, methodological variations should be carefully considered. Differences of less than 0.5 logs are not considered significant. A decrease from 4.3 to 3.9 logs, for example (corresponding to a decrease from approximately 20,000 to 8,000 viral copies/ml) does not necessarily signify a drop in viral load. The same holds for increases in viral load. Changes of up to threefold can therefore be irrelevant. Patients should be made aware of this.

Considerable differences exist between the methods (Coste 1996) and to change from one method to another is therefore generally not advisable. The results obtained by bDNA are usually lower than the PCR by a factor of 2. Different subtypes are also detected with varying success according to the method employed (Parekh 1999). One should be particularly cautious in patients from Africa and Asia with non-B subtypes in whom the viral load at first presentation can be unexpectedly low. In such cases, use of a different assay may actually be indicated. However, newer versions with improved primers are probably superior in measuring even unusual HIV subtypes with adequate sensitivity.

All assays have a linear dynamic range, outside of which precise numbers are not so reliable. The following rule applies: use one method, one laboratory. The laboratory should be experienced and routinely perform a sufficiently large number of tests. Measurement should take place as soon as possible after blood withdrawal, and correct collection and shipping of centrifuged plasma is also important (contact the laboratory ahead of time on these issues).

Tabelle 11.1. Methods of measurement.



Detection limit (co-pies/ml)

Linear Range (copies/ml)

Roche Diagnostics

COBAS TaqMan HIV-1 Test; v2.0




Siemens Healthcare Diagnostics

Versant HIV-1 RNA 1.0 Assay (kPCR)




Abbott Molecular

Abbott RealTime HIV-1




Siemens Healthcare Diagnostics

Versant HIV-1 RNA 3.0 Assay (bDNA)





NucliSENS EasyQ HIV v. 2.0




Influencing factors

Apart from methodological variability a host of other factors may influence levels of viral load including vaccinations and concurrent infections. During active OIs viral load is often high. One study showed a 5- to 160-fold elevated viral load during active tuberculosis (Goletti 1996). Viral load can also increase significantly during syphilis and declines after successful treatment (Buchacz 2004, Kofoed 2006, Palacios 2007). In a large retrospective study, 26% of transient viremia in patients on ART were caused by intercurrent infections (Easterbrook 2002). In these situations, determining the viral load does not make much sense.

Following immunizations, for instance for influenza (O’Brien 1995) or pneumococcus (Farber 1996), the viral load may be transiently elevated (Kolber 2002). As the peak occurs one to three weeks after immunization, routine measurements of viral load should be avoided within four weeks of immunization. It should be noted that not every increase is indicative of virologic treatment failure and resistance. Slight transient increases in viral load, or blips, are usually of no consequence, as numerous studies in the last few years have shown (see chapter on Goals and Principles of Therapy). The possibility of mixing up samples always has to be considered. Unusually implausible results should be double-checked with the laboratory, and if no cause is found there, they need to be monitored – people make mistakes. Should there be any doubt on an individual result; the lab should be asked to repeat the measurement from the same blood sample.

Viral kinetics on ART

The introduction of viral load measurement in 1996-1997 fundamentally changed HIV therapy. The breakthrough studies by David Ho and his group showed that HIV infection has significant in vivo dynamics (Ho 1995, Perelson 1996). The changes in viral load on antiretroviral therapy clearly reflect the dynamics of the process of viral production and elimination. The concentration of HIV-1 in plasma is usually reduced by 99% as early as two weeks after the initiation of ART (Perelson 1997). In one large cohort, the viral load in 84% of patients was already below 1000 copies/ml after four weeks. The decrease in viral load follows biphasic kinetics. In the first phase, i.e., within the first three to six weeks, an extremely rapid drop occurs, followed by a longer phase during which the viral load gradually decreases further (Wu 1999).

The higher the viral load at initiation of therapy, the longer it takes to drop below the level of detection. In one study, the range was between 15 days with a baseline viral load of 1000 and 113 days with a baseline of 1 million viral copies/ml (Rizzardi 2000). The following figure shows a typical biphasic decrease in viral load after initial high levels.

Numerous studies have focused on whether durable treatment success can be predicted early (Thiabaut 2000, Demeter 2001, Kitchen 2001, Lepri 2001). In a study on 124 patients, a decrease of less than 0.72 logs after one week was predictive of virologic treatment failure in more than 99% of patients (Polis 2001). According to another prospective study, it is possible to predict virologic response at 48 weeks even after 7 days (Haubrich 2007). However, this has little clinical relevance, and in our opinion it is pointless to start measurement of viral load only one or two weeks after initiation of therapy.


Figure 1: Typical biphasic decrease in viral load on ART. Viral load was initially very high, and reached a level below 50 copies/ml only at week 32. Note the temporary increase at week 24, which is possibly due to methodological variability. ART was not changed.

We recommend to measure viral load every four weeks until it has dropped to below detection of 20-50 copies/ml. Once that is achieved, measurement every three to four months is enough. Eventually, longer intervals are possible (Chaiwarith 2010). In case of rebound, closer monitoring becomes necessary. Within the first 4 weeks of therapy initiation the viral load should be reduced by a factor of 100, after 3-4 months (6 months if viral load was high) it should be below the level of detection.

Viral load can also be measured fairly reliably in body fluids other than blood or plasma (for example cerebrospinal, vaginal or seminal fluid). However, such tests are usually performed for scientific purposes and are not officially licensed for other reasons.

Practical tips for dealing with viral load (see chapter Goals and Principles of Therapy)

  • Use only one assay, if possible.
  • Use only one experienced laboratory, if possible, no home-brewed assays.
  • Watch for assay variability (up to half a log) and explain this to the patient.
  • Monitor viral load every four weeks with new ART until the viral load is below the level of detection (50 copies/ml).
  • Then measure viral load sparingly – on successful ART every three months may be sufficient.
  • Not on ART, measurement every three months is usually sufficient.
  • Do not measure shortly after vaccinations or with concurrent infections.
  • Implausible results should be rechecked after 2-4 weeks.
  • Consider differences between subtypes (in some cases it may be useful to use another method).

CD4 T cells

CD4 T cells are T lymphocytes that express the CD4 receptor on their surface. This lymphocyte subpopulation is also referred to as T helper cells. Alongside viral load, measurement of the CD4 T cell level is the most important parameter or surrogate marker in HIV medicine. It allows for a reliable estimate of the individual risk of developing AIDS. All HIV-positive patients should have a CD4 T cell measurement every six months. Two reference values are generally accepted: above 400-500 CD4 T cells/µl, severe AIDS-related diseases are very rare; below 200 CD4 T cells/µl, the risk of AIDS-related morbidity increases significantly with increased duration of immunosuppression. Most AIDS-related illnesses occur below 100 CD4 T cells/µl.

Several points should be considered when measuring CD4 T cells (usually by flow cytometry). Blood samples should be processed within 18 hours. The lower normal values are between 400 and 500 cells/µl, depending on the laboratory. Samples should always be sent to the same (experienced) laboratory. The same applies for viral load as for CD4 T cells: the higher the level, the greater the variability. Differences of 50-100 cells/µl are not unusual. In one study, the 95% confidence intervals with a real value of 500 cells/µl were between 297 and 841 cells/µl. At 200 CD4 T cells/µl, the 95% confidence interval was between 118 and 337 cells/µl (Hoover 1993).

Measurement of CD4 T cells should only be repeated in the case of highly implausible values. As long as the viral load remains below the level of detection, there is no need to be concerned even with decreases in CD4 T cells. In such cases, the relative values (CD4 percentages) and the CD4/CD8 ratio (ratio of CD4 to CD8 T cells) should be referred to; these are usually more robust and less prone to fluctuation. As a general point of reference, with values above 500 CD4 T cells/µl, fluctuations of more than 29% are to be expected, with less than 200 CD4 T cells/µl fluctuations of less than 14%. Individual laboratories may define the normal ranges for the relative values and the ratio differently. If there are considerable discrepancies between absolute and relative CD4 T cells, any decisions involving treatment should be carefully considered – if in doubt, it is better to check the values again. The remaining differential blood count should also be scrutinized carefully – is leucopenia or leukocytosis present?

Clinicians sometimes forget that the result of the CD4 T cell count is of existential importance for the patient. To go to the doctor and discuss the test results can involve a great deal of stress for many patients. Insensitively informing the patient of a supposedly bad result can lead to further negative results. From the start, patients must be informed about the possible physiological and method-related variability of laboratory tests. In the case of unexpectedly good results, every effort should be made to contain euphoria. In the long run, this saves time and discussions, and the patient is spared unnecessary ups and downs. We do not consider it advisable for non-physician personnel (without extensive HIV experience) to inform patients of results.


Figure 2: Slow decline of the absolute and relative (dashed line) CD4 T cells/µl over almost ten years in a treatment-naïve patient. Note the variations in the absolute numbers.

Once CD4 T cell counts within the normal range are reached in addition to adequate viral suppression, measurements every six months should suffice, in our opinion. The probability of CD4 T cells dropping to values below 350/µl is extremely low in such cases (Phillips 2003). Patients who might sometimes insist on more frequent monitoring of immune status can be assured that there are usually no detrimental changes in the CD4 T cell count as long as HIV remains suppressed.

Influencing factors

Several other factors can influence CD4 T cell counts apart from laboratory-related variables. These include concurrent infections, leucopenia of varying etiology and steroids or other immunosuppressive therapies. Extreme exertion, surgical procedures or pregnancy can also lead to lower values. Even diurnal variation occurs; CD4 T cells are lower at noon, and highest in the evening around 8 p.m. (Malone 1990). Psychological stress seems to play a negligible role, even though patients often assume the contrary.

Kinetics of CD4 T cells on ART

Similarly to viral load, a biphasic increase in CD4 T cells occurs following the initiation of ART (Renaud 1999, Le Moing 2002), with a rapid increase within the first three to four months and a much slower rise thereafter. In a study of almost 1000 patients, the CD4 T cell count increased by 21/µl per month during the first three months. In the following 21 months, this rate was only 5.5 CD4 T cells/µl per month (Le Moing 2002). The initial rapid increase in CD4 T cells is probably due to redistribution, which is followed by the new production of naïve T cells (Pakker 1998). Diminished apoptosis may also play a role (Roger 2002).

It is still being debated whether the immune system steadily continues its recovery even after a long period of viral suppression, or whether a plateau is reached after three to four years beyond which there is less improvement (Smith 2004, Viard 2004).

Several factors can influence the extent of immune reconstitution during ART. The degree of viral suppression is crucial – the lower the viral load, the more pronounced the effect (Le Moin  2002). The absolute increase is higher if CD4 T cell counts were high at the start of ART (Kaufmann 2000). Naïve T cells still present at initiation of therapy are a particularly important factor for long-term immune reconstitution (Notermans 1999).

Age is also important (Grabar 2004). The larger the thymus and the more active the process of thymopoiesis, the more significant the rise in CD4 T cells is likely to be (Kolte 2002); due to age-related degeneration of the thymus, CD4 T cells in older patients do not increase as much as those in younger ones (Viard 2001). However, we have seen both 20 year-old patients with very poor CD4 T cell count recovery and 60 year-old patients with very good, above average increases in CD4 T cells. The regenerative capacity of the human immune system seems to vary considerably, and no method to date has been capable of reliably predicting this capacity.

It is possible that some antiretroviral therapies such as ddI+tenofovir are associated with less immune reconstitution than others. In addition, current studies evaluate if immune reconstitution is better during treatment with CCR5 antagonists. Immunosuppressive concurrent medications should also be considered (see chapter on Goals and Principles of Therapy).

Practical tips for dealing with CD4 T cells

  • As with viral load: use only one (experienced) laboratory.
  • The higher the values, the greater the variability (consider numerous factors) – compare the relative (percentage) values and CD4/CD8 ratio with previous results.
  • Do not disconcert the patient when there are apparent decreases – if viral suppression is sufficient, the drop is usually not HIV-related. Only highly implausible results should be repeated.
  • If the viral load is below the level of detection, three-monthly measurements of CD4 T cells are sufficient.
  • In the presence of good viral suppression and normal CD4 T cells, CD4 T cells (not viral load) may also be checked less frequently.
  • CD4 count and viral load should be discussed with the physician. Do not leave patients alone with their results.

Beyond the measurement of the CD4 T cell count and lymphocyte subpopulations, a number of other assays allow detailed testing of the qualitative or functional capacity of the immune system, for example in response to specific antigens (Telenti 2002). These often cumbersome methods are not currently necessary for routine diagnostics and their use remains questionable. However, they could one day help to better describe individual immune status and, for example, identify those patients who are at risk of developing opportunistic infections despite good CD4 cell counts.

Routine checks – What else should be monitored?

Besides the CD4 T cell count and viral load several other parameters should be monitored in the HIV-positive patient. The following recommendations apply to clinically asymptomatic patients with normal results on routine laboratory evaluation, who have been on stable treatment for several months or who are not taking antiretroviral therapy. Of course, if treatment is started or changed or if the patient develops complaints more frequent monitoring is required. Depending on the problem additional tests may be necessary.

A complete physical examination should be performed regularly, and this often leads to the discovery of important findings such as Kaposi lesions or mycoses (thrush). The lower the CD4 T cells, the more frequently patients should be examined.

In patients with less than 200 CD4 T cells/µl, we usually perform fundoscopies every three to six months to exclude CMV retinitis. Close cooperation with an HIV-experienced ophthalmologist is essential. The better the CD4 T cells, the less often fundoscopies are necessary – in our opinion when CD4 counts have normalized these can be stopped completely. In contrast, regular gynecological examinations with PAP smears are recommended regardless of CD4 count. Many experts now also recommend rectal examination (including proctoscopy) for the early detection of precancerous lesions and anal cancer.

However, such guidelines or recommendations can be interpreted very differently. In our opinion in cases of good immune status unless there is a specific suspicion routine X-rays, ultrasound examinations (exception: patients with chronic hepatitis, as hepatocellular carcinoma is not rare in such cases), multiple serologies or lactate measurements are not necessary. An annual ECG is only indicated in our view in patients with a specific risk profile (see chapter on HIV and Cardiac Disease). The tuberculin test (the Mendel-Mantoux skin test with 5 IE once a year) should only be repeated if it is negative initially.

Table 11.2. Minimal evaluations per year in stable asymptomatic patients.

Patient on ART

per year


per year

Blood count, LDH, ALT, AST, creatinine, bilirubin, AP, lipase, GGT, glucose

4-6 x

2-4 x

Viral load

4 x

2-4 x

CD4 T cells

2-4 x

2-4 x


1-2 x

1 x

Physical examination, urine status

2-4 x

1-2 x

Gynecological examination

1 x

1 x

Funduscopy if CD4 T cells <200/µl

1-2 x

4 x

With regard to the growing age of the HIV population, it is essential not to forget cancer screening. In many countries, for example, colonoscopy is recommended for early detection of colorectal cancer for every individual older than 50-55 years (colonoscopy should be performed every 10 years). For further information see WHO website,

Therapeutic Drug Monitoring (TDM)

Plasma levels of many antiretroviral drugs may vary considerably for diverse reasons (e.g., compliance, metabolism, absorption). Measurement of drug concentrations in serum or plasma is also referred to as therapeutic drug monitoring (TDM).

Sufficient plasma levels are essential for success of virologic treatment (Acosta 2000). In the VIRADAPT Study adequate PI concentrations were even more crucial than knowledge of resistance mutations (Durant 2000). The importance of sufficient plasma levels has also been shown for NNRTIs (Marzolini 2001, Veldkamp 2001). This information however dates to the early years of ART.

Whether TDM still improves virologic response today, is not clearly validated (Kredo 2009). Only a few large randomized studies exist that have provided data regarding this question (Review: Liu 2010). One of the few randomized studies could only show a trend to virologic (Best 2007). TDM remained without any effect in another study with patients receiving boosted PIs (Demeter 2009).

On the other hand, very high plasma levels correlate with a higher rate of side effects. Reported renal problems with indinavir (Dielemann 1999), gastrointestinal disturbances with ritonavir (Gatti 1999), hepatotoxicity with nevirapine (Gonzalez 2002) or CNS problems with efavirenz (Marzolini 2001) were all associated with high plasma levels. For this reason, TDM will remain a tool for therapy observation: not every interaction between antiretroviral drugs or with concomitant drugs has been investigated.

Measurement of plasma levels may currently be reasonable in the following situations (German-Austrian ART guidelines):

  • Complex drug combinations including boosted PIs
  • Patients with very high or low body weight
  • Side effects
  • Treatment failure (resistance?)
  • Suspected absorption or adherence problems
  • Severe liver or renal diseases
  • Art with children, pregnancy
  • Once daily regimen
  • Use of new drugs (unknown interactions)

Several problems associated with TDM limit its broader use. The measurement of NRTIs, for example, is not possible since they are converted to the active metabolites only intracellularly. Intracellular measurements are difficult and are not available in routine clinical practice. There is no valid data available for new antiretroviral agents such as T-20, raltegravir or maraviroc.

Measuring NNRTIs or PIs may therefore currently determine levels of only one component of a failing combination. Further problems include not only viral strains with different levels of resistance, different inhibitory concentrations, variable protein binding, and time-dependent variability of plasma levels, but also methodological problems with the assays, as well as the lack of clearly defined limits. Many uncertainties thus remain in the assessment of therapeutic drug plasma levels. Until data from randomized studies is available, proving the clinical value of TDM, both the measurement and interpretation of results should be left to specialized centers.


Acosta EP, Kakuda TN, Brundage RC, Anderson PL, Fletcher CV. Pharmacodynamics of HIV type 1 protease inhibitors. Clin Infect Dis 2000, Suppl 2:S151-9.

Best BM, Goicoechea M, Witt MD, et al. A randomized controlled trial of therapeutic drug monitoring in treatment-naive and -experienced HIV-1-infected patients. J AIDS 2007;46:433-42.

Buchacz K, Patel P, Taylor M, et al. Syphilis increases HIV viral load and decreases CD4 cell counts in  HIV-infected patients with new syphilis infections.  AIDS 2004, 18:2075-2079.

Chaiwarith R, Praparattanapan J, Salee P, et al. Frequency of HIV-RNA Monitoring: impact on outcome of antiretroviral therapy. Abstract 500, 17th CROI 2010, San Francisco.

Clevenbergh P, Mouly S, Sellier P, et al. Improving HIV infection management using antiretroviral plasma drug levels monitoring: a clinician’s point of view. Curr HIV Res 2004, 2:309-21.

Coste J, Montes B, Reynes J, et al. Comparative evaluation of three assays for the quantitation of HIV type 1 RNA in plasma. J Med Virol 1996, 50:293-302.

Demeter LM, Hughes MD, Coombs RW, et al. Predictors of virologic and clinical outcomes in HIV-1-infected patients receiving concurrent treatment with indinavir, zidovudine, and lamivudine. ACTG Protocol 320. Ann Intern Med 2001, 135: 954-64.

Demeter LM, Jiang H, Mukherjee AL, et al. A randomized trial of therapeutic drug monitoring of protease inhibitors in antiretroviral-experienced, HIV-1-infected patients. AIDS 2009, 23:357-68.

Dieleman JP, Gyssens IC, van der Ende ME, de Marie S, Burger DM. Urological complaints in relation to indinavir plasma concentrations in HIV-infected patients. AIDS 1999, 13:473-8.

Durant J, Clevenbergh P, Garraffo R, et al. Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study. AIDS 2000, 14:1333-9.

Easterbrook PJ, Ives N, Waters A, et al. The natural history and clinical significance of intermittent viraemia in patients with initial viral sup-pression to < 400 copies/ml. AIDS 2002; 16:1521-7.

Farber CM, Barath AA, Dieye T. The effects of immunization in HIV type 1 infection. N Engl J Med 1996, 335:817; discussion 818-9.

Gatti G, Di Biagio A, Casazza R, et al. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS 1999, 13:2083-9.

Ghani AC, de Wolf F, Ferguson NM, et al. Surrogate markers for disease progression in treated HIV infection. J Acquir Immune Defic Syndr 2001; 28: 226-31.

Goletti D, Weissman D, Jackson RW, et al. Effect of Mycobacterium tuberculosis on HIV replication. Role of immune activation. J Immunol 1996, 157:1271-8.

Gonzalez de Requena D, Nunez M, Jimenez-Nacher I, Soriano V. Liver toxicity caused by nevirapine. AIDS 2002, 16:290-1.

Grabar S, Kousignian I, Sobel A, et al. Immunologic and clinical responses to highly active antiretroviral therapy over 50 years of age. Results from the French Hospital Database on HIV. AIDS 2004, 18:2029-2038.

Haubrich R, Riddler S, Ribaudo H, et al. Initial viral decay to assess the relative antiretroviral potency of PI-, NNRTI-, and NRTI-sparing regimens for first line therapy of HIV-1 infection: ACTG 5160s. Abstract 137, 14th CROI 2007, Los Angeles. Abstract:

Ho DD, Neumann AU, Perelson AS, et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373:123-6.

Hoover DR. Would confirmatory retesting of CD4+ cells to verify AIDS status be too expensive? J Acquir Immune Defic Syndr 1993, 6:537-9.

Hughes MD, Johnson VA, Hirsch MS, et al. Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. ACTG 241 Protocol Virology Substudy Team. Ann Intern Med 1997; 126: 929-38.

Kaufmann GR, Bloch M, Zaunders JJ, Smith D, Cooper DA. Long-term immunological response in HIV-1-infected subjects receiving potent antiretroviral therapy. AIDS 2000, 14: 959-69.

Kitchen CM, Kitchen SG, Dubin JA, Gottlieb MS. Initial virological and immunologic response to HAART predicts long-term clinical outcome. Clin Infect Dis 2001; 33: 466-72.

Kofoed K, Gerstoft J, Mathiesen LR, Benfield T. Syphilis and human immunodeficiency virus (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sex Transm Dis 2006;33:143-8.

Kolber MA, Gabr AH, De La Rosa A, et al. Genotypic analysis of plasma HIV-1 RNA after influenza vaccination of patients with previously undetectable viral loads. AIDS 2002, 16: 537-42.

Kolte L, Dreves AM, Ersboll AK, et al. Association between larger thymic size and higher thymic output in HIV-infected patients receiving HAART. J Infect Dis 2002, 185:1578-85.

Kredo T, Van der Walt JS, Siegfried N, Cohen K. Therapeutic drug monitoring of antiretrovirals for people with HIV. Cochrane Database Syst Rev 2009, CD007268. Review.

Le Moing V, Thiebaut R, Chene G, et al. Predictors of long-term increase in CD4(+) cell counts in HIV-infected patients receiving a protease inhibitor-containing antiretroviral regimen. J Infect Dis 2002, 185: 471-80.

Lepri AC, Miller V, Phillips AN, et al. The virological response to HAART over the first 24 weeks of therapy according to the pre-therapy viral load and the weeks 4-8 viral load. AIDS 2001, 15: 47-54.

Liu X, Ma Q, Zhang F. Therapeutic drug monitoring in highly active antiretroviral therapy. Expert Opin Drug Saf 2010, 9:743-58.

Lyles RH, Munoz A, Yamashita TE, et al. Natural history of HIV type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. J Infect Dis 2000, 181:872-880.

Maggiolo F, Migliorino M, Pirali A. Duration of viral suppression in patients on stable therapy for HIV-1 infection is predicted by plasma HIV RNA level after 1 month of treatment. J Acquir Immune Defic Syndr 2000, 25:36-43.

Malone JL, Simms TE, Gray GC, et al. Sources of variability in repeated T-helper lymphocyte counts from HIV type 1-infected patients: total lymphocyte count fluctuations and diurnal cycle are important. J Acquir Immune Defic Syndr 1990, 3:144-51.

Marzolini C, Telenti A, Decosterd LA, et al. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 2001, 15: 71-5.

Mellors JW, Munoz AM, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997, 126:946-954.

Napravnik S, Poole C, Thomas JC, Eron JJ Jr. Gender difference in HIV RNA levels: a meta-analysis of published studies. J Acquir Immune Defic Syndr 2002, 31:11-9.

Notermans DW, Pakker NG, Hamann D, et al. Immune reconstitution after 2 years of successful potent ART in previously untreated HIV type 1-infected adults. J Infect Dis 1999, 180: 1050-6.

O’Brien WA, Grovit-Ferbas K, Namazi A, et al. HIV-type 1 replication can be increased in peripheral blood of seropositive patients after influenza vaccination. Blood 1995, 86:1082-9.

Pakker NG, Notermans DW, de Boer RJ, et al. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nat Med 1998, 4: 208-14.

Palacios R, Jimenez-Onate F, Aguilar M, et al. Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients. J Acquir Immune Defic Syndr 2007;44:356-9.

Parekh B, Phillips S, Granade TC, et al. Impact of HIV type 1 subtype variation on viral RNA quantitation. AIDS Res Hum Retroviruses 1999, 15:133-42.

Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997, 387:188-91.

Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996, 271:1582-6.

Phillips A, CASCADE Collaboration. Short-term risk of AIDS according to current CD4 cell count and viral load in antiretroviral drug-naive individuals and those treated in the monotherapy era. AIDS 2004, 18:51-8.

Phillips AN, Youle M, Lampe F, et al. CD4 cell count changes in individuals with counts above 500 cells/mm and viral loads below 50 copies/ml on antiretroviral therapy. AIDS 2002; 16: 1073-5.

Polis MA, Sidorov IA, Yoder C, et al. Correlation between reduction in plasma HIV-1 RNA concentration 1 week after start of antiretroviral treatment and longer-term efficacy. Lancet 2001,  358: 1760-5

Renaud M, Katlama C, Mallet A, et al. Determinants of paradoxical CD4 cell reconstitution after protease inhibitor-containing antiretroviral regimen. AIDS 1999, 13:669-76.

Rizzardi GP, DeBoer RJ, Hoover S, et al. Predicting the duration of antiretroviral treatment needed to suppress plasma HIV-1 RNA. J Clin Invest 2000, 105:777-782.

Roger PM, Breittmayer JP, Durant J, et al. Early CD4(+) T cell recovery in HIV-infected patients receiving effective therapy is related to a down-regulation of apoptosis and not to proliferation. J Infect Dis 2002, 185: 463-70.

Smith CJ, Sabin CA, Youle MS, et al. Factors influencing increases in CD4 cell counts of HIV-positive persons receiving long-term highly active antiretroviral therapy. J Infect Dis 2004, 190:1860-8.

Smith CJ, Staszewski S, Sabin CA, et al. Use of viral load measured after 4 weeks of highly active antiretroviral therapy to predict virologic outcome at 24 weeks for HIV-1-positive individuals. J AIDS 2004, 37:1155-1159.

Stellbrink HJ, Schewe CK, Hoffmann C, Wolf E. Is there a harmless level of plasma viremia in untreated HIV infection? CD4+ T cells in the long-term follow-up of elite controllers and controls. Abstract 351, 14th CROI 2008, Boston

Telenti A. New developments in laboratory monitoring of HIV-1 infection. Clin Microbiol Infect 2002, 8:137-43.

Thiebaut R, Morlat P, Jacqmin-Gadda H, et al. Clinical progression of HIV-1 infection according to the viral response during the first year of antiretroviral treatment. AIDS 2000, 14: 971-8.

Veldkamp AI, Weverling GJ, Lange JM, et al. High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals. AIDS 2001; 15: 1089-95.

Viard JP, Burgard M, Hubert JB, et al. Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level. AIDS 2004, 18:45-9.

Viard JP, Mocroft A, Chiesi A, et al. Influence of age on CD4 cell recovery in HIV-infected patients receiving HAART: evidence from the EuroSIDA study. J Infect Dis 2001, 183: 1290-4.

Walter EA, Gilliam B, Delmar JA, et al. Clinical implications of identifying non-B subtypes of HIV type 1 infection. Clin Infect Dis 2000, 31:798-802.

Wu H, Kuritzkes DR, McClernon DR, et al. Characterization of viral dynamics in HIV type 1-infected patients treated with combination antiretroviral therapy: relationships to host factors, cellular restoration, and virologic end points. J Infect Dis 1999, 179: 799-807.

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Filed under 6.11. Monitoring, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy

6.12. Prevention, compliance, costs

– Christian Hoffmann –

In the following, some aspects of antiretroviral therapy will be discussed in more detail that have only been mentioned briefly in previous chapters.


About 30 years after AIDS was first described a prophylactic vaccination remains a distant prospect. In 2007 two highly promising vaccine studies were prematurely interrupted. It seems doubtful now that a vaccine to effectively prevent HIV infection will be discovered anytime soon – the moderate but surprisingly successful RV144 vaccine study will not change that (Rerks-Ngarm 2009, see chapter on Preventive Vaccination). Several experts believe that a promising vaccine candidate does not exist presently (Desrosiers 2008, Nathanson 2008) while others say it is time to get used to the fact that a vaccine may never come. Neither blind hope nor time schedules have proved very helpful. Some vaccine studies up until now can in fact be regarded as counter-productive, fatiguing both sponsors and the community.

Considering all this, prevention will continue to be the central means of controlling the HIV epidemic. However, common prevention strategies focused on the ABC guidelines (abstinence, be faithful, condom use) have reached their limits. In 2009 UNAIDS declared a worldwide increase of 2.2 million new infections. In every major city in the US or in Europe syphilis endemics in HIV-infected patients have been reported. In Germany, for example, the number of new infections among men who have sex with men (MSM) has been almost continuously rising since 2001.

It seems clear that advertisements and brochures alone are not the solution, especially when these simple publicity mechanisms are not maintained. High-risk groups are not being reached effectively. Prevention remains an arduous business and success is not immediately visible nor is it profitable. Sexual behavior is not easily modified by a few advertisements or brochures.

For some time, preventive medicine in HIV has been taking completely new and sometimes unusual paths to reach focus groups. Terms such as serosorting, seropositioning, dipping or strategic positioning show that the medical world is learning to face reality. People have sex and not everyone cares about, follows, or can follow guidelines. Recent studies with serosorting, choosing sexual partners according to perceived HIV serostatus, show that new prevention strategies can be developed (Morin 2008).

The following focuses mainly on medical prevention strategies. In 2010 there have been groundbreaking new findings in this area regarding PrEP and microbicides.

ART & Prevention

Antiretroviral therapy is an important contribution to prevention, possibly the most important (Hosseinipour 2002). As these studies show:

  • In a group of 415 HIV-discordant couples in Uganda 90 new infections were diagnosed over a period of 30 days. Not a single infection was caused by an infected partner with a viral load below 1500 copies/ml. With every additional log of HIV RNA, infection risk increased by a factor of 2.45 (Quinn 2000).
  • In a study in Thailand with 493 HIV-discordant couples, the factor was 1.81. No infection from a partner with less than 1094 copies/ml was recorded (Tovanabutra 2002).
  • In a study in Spain with 393 heterosexual HIV-discordant couples, a transmission rate of 8.6% was observed between 1991 and 2003. No infection was recorded with infected partners who were receiving combination ART.
  • In a group of 534 MSM in San Francisco, infectiousness based on the probability of transmission per couple decreased by 60% between 1994 and 1998 (Porco 2004). The HIV incidence decreased in spite of the reported higher number of partners and risk contacts, even though not all of the HIV-infected partners were on antiretroviral therapy.
  • In a Spanish study with 62 HIV-discordant couples (22 HIV-infected women, 40 HIV-infected men, all of them on ART), 76 “natural” pregnancies were diagnosed. Not a single HIV infection of a non-infected partner was recorded (Barreiro 2006).

The above-mentioned clinical studies show clearly that the lower the viral load in the plasma, the less infectious the patient. In an ongoing meta-analysis in 11 cohorts with 5021 heterosexual couples (and 461 HIV transmissions) the transmission rate of patients on ART was 0.46 per 100 person years (5 cases). Not one transmission was detected from anyone who was below 400 copies/ml (Attia 2009).

Test and treat?

At the end of 2008 a statistical paper caused great discussion. A research group led by the Director of WHO Kevin De Cock calculated how to, at least theoretically, curtail and even eliminate the worldwide HIV epidemic (Granich 2008). For this ambitious goal they concentrated totally on the preventive effect of antiretroviral therapies. They compared the common treatment strategy used today, beginning ART only on symptomatic patients or on those who have less than a certain number of CD4 T cells, to a theoretical strategy that seems simple enough. Every person is tested for HIV once a year and if found positive, starts ART immediately, irrespective of CD4 T cells or viral load. The study was based on population data in South Africa, where 17% of the adult population is HIV-infected and on data from a successful intervention in Malawi. Other preconditions of the calculation model are that infectiousness of treated versus not-treated patients was estimated at 1%. The case-reproduction number, the so called R0 number of new infections caused by one infection, was crucial for this calculation. The corresponding simple assumption that R0 of <1 is required in order to reduce the incidence and to eventually eliminate HIV means that an incidence rate of less than one new case per 1000 person years was determined in order to eliminate HIV.

Reality shows different results. At present, every untreated HIV-infected individual causes another 7 HIV infections (R0=7) in the course of their lifetime. R0 could be reduced to 4 if every person received regular treatment with therapy starting at 200 CD4 T cells/µl, or even to 3 if therapy starts at 350 CD4 T cells/µl. However, an R0 reduction to less than 1 is impossible by this method and curtailing the epidemic with ART alone remains unrealistic. This could change however, with regular testing and immediate treatment of positively-diagnosed individuals – elimination of the epidemic could be possible by 2020, even in a country as severely affected as South Africa. Compared with common practice today where ART is begun only at a certain level of CD4 T cells, immediate treatment could reduce AIDS mortality to half today’s number by 2050. Calculations showed that this initially more expensive strategy could start to be cost-saving by around 2032.

The comments to the WHO publication ranged from “provocative” (Cohen 2008) to “extremely radical” (Garnett 2008). Critics raised concerns over the risks and the absence of ethics (would all actors agree? Could a restricted individual autonomy be achieved? Can changes in sexual habits be maintained?), medical (compliance problems, the dangers of possible resistance, the side effects and “overtreatment” – starting too early) as well as financial (South Africa would have to triple their financial commitments) considerations.

Such calculations are not new. Other groups have arrived at similar results in the past (Velasco-Hernandez 20002, Montaner 2006). What is new is that antiretroviral therapies today are potentially more user-friendly and such programs are probably easier to put into practice than just a few years ago.

In addition, people are realizing that the current preventive measures can only improve slowly and that neither vaccines nor microbicides can be expected in the near future. At present, approximately 80% of the population in sub-Saharan Africa is not aware of their infection. More than 90% do not know if their sexual partners are infected – an invitation for further spread of the epidemic.

Juggling figures like this may seem unhelpful at first. Despite all objections regarding methodological, ethical, financial or logistic considerations, etc., facing 2.2 million new infections per year, a number that is not likely to decline much (if at all) in the near future, and the failure of several vaccine and prevention studies, one thing has become clear. Antiretroviral therapy has turned into one of the most important components of prevention.

Such initiatives like that of the WHO must be continued, and new and unusual strategies must be continually developed. It cannot do harm to bring more therapy to the 6.7 million people, worldwide, the number who by the end of 2007 desperately needed ART and were not receiving it (see chapter on Global Access).

ART & viral load in other body fluids

Do viral load in plasma and viral load in other body fluids correlate?  Here are some data:

  • In a study from Italy the viral load on PI-containing ART regimens decreased by several logs in plasma as well as in semen (Liuzzi 1999).
  • In a Swiss study with 114 male patients with plasma viremia under 400 copies/ml on ART, only 2 (2%) isolated viral loads were detected in semen, compared to 67% in untreated control groups.
  • In 205 HIV-infected women with plasma viremia under 400, 400-9999 and over 10,000 copies/ml, the rate of detectable HIV-1 RNA in the genital tract was 3, 17 and 48%, respectively (Cu-Uvin 2000). In 7 ART-naïve women, the viral load decreased by 0.7–2.1 logs within the first 14 days of ART. Similar results were achieved with 11 Brazilian female patients (Vettore 2006).
  • In a group of 290 women with plasma viremia under 500 copies/ml, 44 (15%) had detectable HIV-1 RNA in cervical smears (Neely 2007). In comparison to PI-containing ART the risk with NNRTIs was double.
  • In a study with 34 females with plasma viremia below 80 copies/ml, all treated with ART for at least 6 months, only one woman showed a viral load over 80 copies/ml in cervical vaginal fluid (CVF) compared to 7 rebounds in plasma (Kwara 2008).
  • Out of 122 samples of cervical vaginal lavage the viral load in the lavage correlated highly with plasma viral load (Fiore 2003). However, in 25% of cases, virus was found in the lavage even when plasma viremia findings proved negative.
  • In a study with 233 MSM (1996–1997), far less virus was found in anorectal smears of those treated with ART. Among those patients with less than 50 copies/ml in plasma, 1/54 (2%) HIV-1 RNA was detected in the anorectal smear. However, in 14/50 (28%) HIV-1 DNA was detected.
  • Among 255 MSM receiving ART with a plasma viral load below 40 copies/ml, 7 patients (3%) showed an isolated viral load in semen (Marcelin 2009). These 7 patients had been on ART for some time and treated with agents detected in semen.
  • In a prospective study on 25 Canadian patients on ART, a viral load in semen was found in 19/116 (14%) samples (Sheth 2009). There was no reference to drug concentration  in seminal fluid.

In conclusion, in most cases, viral load in plasma parallels viral load in other bodily fluids. If the viral load in plasma decreases, so does the RNA in semen or the vaginal fluid within a short time. “Below the limit of detection in plasma” also means “below the limit of detection in other bodily fluids”. In most cases. There are exceptions: in the studies above the variation was between 1 and 14%. Although there are implications that the detected virus in semen is not completely infectious (Nunnari 2002), one cannot rule out the patient being potentially infectious even on successful ART.

Putting together these facts with clinical data, transmission with a low viral load seems unlikely. To date, only a few cases have been recorded in which transmission has taken place despite effective ART (Stürmer 2008). These cases show that there is in fact a residual risk. The question is how to manage that risk.

The EKAF paper

In January 2008 a paper was released by the “Eidgenössische Kommission für Aids-Fragen” (EKAF), the Swiss AIDS commission. Just the title of this paper caused a great stir: “HIV-infected individuals without other STDs on effective antiretroviral therapy are not sexually infectious.” The original manuscript can be found at

EKAF concluded that HIV-infected individuals do not transmit the disease under three conditions:

1. ART is adhered to and monitored by a clinician

2. The viral load has been below detection for at least six months

3. There is no other STD

This first official statement from public authorities on this subject had a major impact. Despite its caveats, critics feared that this publication could be misunderstood as an all-clear signal resulting in people being less careful and unnecessarily exposing themselves to risks of HIV infection.

Critics say that the data is not sufficient, especially for the risk of anal sexual contacts. The probability of infection is certainly under 1:100,000, but nevertheless not zero (Wilson 2009). The preventive effect of ART may be endangered by higher risk taking. According to mathematical models, a 10% rise in risk behavior could counter the effects of ART (Blower 2001, Law 2001). However, a meta-analysis came to the conclusion that ART does not increase risk behavior of the patient, even if the viral load is below detection (Crepaz 2004).

HIV clinicians must be prepared for this discussion. Patients are asking more questions: do I have to use a condom for the rest of my life? Here, it is better to give individualized advice. It depends greatly on the non-infected partner as well, as he or she should not be pressured. On the other hand, information of this type can be a relief for many patients and their partners. The EKAF paper may also motivate high-risk patients to finally start antiretroviral treatment (preventing more infections rather than causing new ones initially feared by the release of the paper).

However, it must be repeated that the EKAF statement refers only to stable relationships. Safer sex is still recommended, especially with occasional sexual contacts to avoid other sexually transmittable diseases.

Medical prevention strategies besides ART


Circumcision of the male foreskin reduces the risk of infection for several diseases in unprotected sexual intercourse (Weiss 2006). At least three randomized trials with heterosexual males in Uganda, Kenya and South Africa demonstrated this in recent years for HIV as well. Remarkably similar results were achieved (Table 12.1).

Table 12.1. Large randomized studies on circumcision.



Main Results

Reduction of Transmission risk

(Bailey 2007)


Two–Year HIV Incidence 2.1%  (95% CI 1.2-3.0) vs 4.2% (95% CI 3.0-5.4)


(Gray 2007)


Over 24 months HIV incidence
0.66 vs 1.33/100 person years


South Africa
(Auvert 2005)


Over 18 months HIV incidence
0.85 vs 2.10/100 person years


TR = Transmission Risk, partly different definition/calculation

A meta-analysis of these studies shows a relative risk of 0.44 for circumcision (Mills 2008). The NNT (number needed to treat) required to prevent an event reached a relatively low number of 72.

The effect of circumcision is explained by the presence of CD4-positive Langerhans cells and primary HIV target cells in the male foreskin. Circumcision reduces the frequency of genital HSV-2 infection (Tobian 2008), which however does not explain the protective effect (Gray 2009). An estimated 2 million HIV infections in Africa alone could be prevented in the next few years (Williams 2006). The WHO recommends circumcision as a preventive means for heterosexual men. A favourable side effect is that fewer HPV-infections are transferred (Serwadda 2010)

Circumcision, however, is not without risk. Complications (infections, postoperative bleeding) occur in 3-4% of cases (Gray 2007). Sexual behavior after circumcision, ethics and logistical problems are only a few aspects (Lie 2006). It must be noted that circumcision reduces the risk for male but not for female partners. The randomized study in Uganda showed a slight increase in infections of the female partners of circumcised males (Waver 2008). This can be mainly explained by couples probably having sexual intercourse earlier than recommended. Several weeks of no-sex are stipulated after the operation.

Is there a protective effect for MSM after circumcision? If there is, the data is less clear compared to the results for heterosexual men. A meta-analysis of 15 greatly varying studies with 53,567 MSM (52% with circumcision) showed no significant difference between circumcised and uncircumcised males (Millet 2008). Another newer study confirms these results (Sanchez 2011).

Preventive treatment of HSV and other diseases

Genital infections clearly increase the risk of acquiring HIV. This applies especially to the human herpes virus 2 (HSV-2). According to a meta-analysis, the risk of HIV increases with HSV-2-seropositivity: when HSV-2 antibodies are detected in the blood, the risk increases in male patients by 2.7 fold and in female patients by 3.1 fold (Freeman 2006). A considerable amount of new HIV infections are due to HSV coinfection, with an estimated 38–69% in female patients and 8–49% in male patients.

Is a reduction of the HIV transmission rate in HIV-negative persons possible by suppression of HSV-2? HPTN 039, a double-blind, randomized, Phase III trial investigated (Celum 2008). In total, 1871 MSM from the USA and Peru and 1380 women from Zimbabwe, Zambia and South Africa received 400 mg acyclovir or placebo twice daily. Enrolled subjects were all HIV-negative and HSV-2-positive at the beginning of the trial. Although less HSV ulcers were observed in the active group, the trial failed to show a decline in HIV incidence in the acyclovir-group, with 3.9/100 person-years compared to 3.3/100 in the placebo group. These disappointing results were confirmed by the Mwanza trial with 821 women in Tanzania, in which again no decline was observed (Watson-Jones 2008). It is still not clear why, however, resistances against acyclovir is unlikely (Watson-Jones 2010).

According to current data, preventing HIV infection with HSV therapy using acyclovir has proven unsuccessful. The prophylactic use of azithromycin, to prevent bacterial STDs also showed no protective effect against HIV (Kaul 2004).

Can the transmission rate be reduced if the HIV-infected partner is treated with acyclovir? A huge study enrolling 3408 discordant African couples showed no effect of the transmission rate, albeit the clearly reduced rate of genital HSV ulcers (Celcum 2010). However, this study did show an interesting side effect, that there is a slight but measurable effect with acyclovir and its derivatives regarding HIV viral load. Compared to placebo, a decline of 0.25 logs was observed. This effect slightly decreased the risk of HIV progression in therapy naïve patients (Lingappa 2010). The transmission rate was obviously not influenced by the reduction in viral load. Resistances were not induced by acyclovir (Baeten 2011).

Antiviral effects were also observed in several other randomized studies. The viral load in blood and cervicovaginal fluids was reduced by 0.26 to 0.53 logs by using acyclovir or valacyclovir (Delany 2009, Nagot 2007, Zuckermann 2007, Baeten 2008, Dunne 2008, Paz-Bailey 2009). These studies may possibly lead to the development of new acyclovir derivatives with improved antiviral potency, provided they respond well to HIV (Vanpouille 2010).

Microbicides, lubricants, diaphragms

Microbicides are chemical agents, mostly of topical application, in the form of gels that kill or immobilize HIV and other diseases. Presently heterogenic mechanisms are being examined. Among them are inactivated agents that inhibit docking to the target cell or antiviral agents. It is required that microbicides are not only inexpensive, easy to apply and non-toxic, but also effective against other STDs, as these increase the risk of HIV-transmission. The CAPRIAL trial (see below) has led to a noticeable revival in this field of research.

Inactive microbicides: Up to now, there is no product that has delivered convincing protective effects in clinical studies. HIV transmission risk in fact increased with nonoxynol-9 (Van Damme 2002) or cellulose sulfate (van Damme 2008).  PRO 2000, which initially seemed promising, had no effect (McCormack 2010). Application of diaphragma and/or lubricants in addition to condomes had no protective effect, as one randomized study showed (Padian 2007).

Antiretroviral Microbicides: A breakthrough in research of microbicides was achieved in the CAPRISA trial in September 2010. CAPRISA was a doubleblind study, in which 889 HIV-negative women in South Africa used 1% tenofovir gel (Abdol Karim 2010). Compared to placebo, HIV incidence was reduced from 9.1 to 5.6/100 years. Transmission risk for women applying the gel regularly was reduced by 54%. This first success (“proof of concept”) has led to a focus on antiretroviral substances in the research of microbicides, such as tenofovir and even the more experimental NNRTIs dapivirine and MIV-150, as well as maraviroc and raltegravir (Review: Mertenskötter 2011).

PrEP (Pre-exposure Prophylaxis)

In the HIV setting, PrEP is an oral prophylactic antiretroviral treatment. Like malaria prophylaxis, it is taken before exposure. PrEP trials are currently being conducted in high-risk groups (i.e., commercial sex workers). Most trials use tenofovir, either alone or in combination with FTC. Such studies, however, have been regarded with criticism. Pressured by activists and others, a study with Cambodian sex workers was interrupted in 2004 and others in Cameroon and Nigeria in 2005 (Cohen 2004, Sing 2005). The researchers involved were accused of not providing sufficient information to the participants and of discontinuing treatment once the study was over.

A similar breakthrough, like the one with microbicides by the CAPRISA trial, was seen with PrEP in the end of 2010. In the iPrEx study, 2499 MSM from six countries received either TDF+FTC or placebo. After a median of 1.2 years, 36 versus 64 infections were observed and the risk for infection was reduced by 44%. Apart from slightly more cases of nausea and weight loss in the verum group, there were no differences. Only in 3/34 patients infected in the verum group, tenofovir or FTC were detected in plasma. One may argue that complete protection is not secured: However, with an alarmingly high number of 2.2 million new infections worldwide, PrEP remains an approach that must be pursued.

Table 12.2: Large randomized study on PrEP, March 2011


Risk group, kind of  PrEP

Status, first results



IDU: tenofovir

fully recruited, 2012

Africa, Partners PrEP Study


discordant couple: tenofovir, Tenofovir+FTC

fully recruited, 2012

Africa, FEM PrEP


women: tenofovir+FTC

49 % recruited, 2013

Africa,  VOICE/ MTN 003


women: tenofovir, tenofovir+FTC, vaginal tenofovir gel

65 % recruited, 2013

Physicians must be prepared for inquiries on PrEP, although some questions still remain that have not been answered by the above study.

How should PrEP be administered? Who will receive the treatment? And who will cover the expense? What about development of resistance in unidentified HIV infection? Will this decrease the use of condoms? Will PrEP be sold on the black market in the near future (and so, with limited adherence programs)? These are only a few aspects to be considered. In Switzerland as well as at the EMA, a commission dealing with these questions has already been set up, although the benefits of PrEP have not yet been scientifically proven.

In conclusion, with dramatically high numbers of continuing infections worldwide, prevention must strike new paths. Strictly Propagating safer sex alone is not enough. Among medical approaches, the use of antiretroviral therapy is the most imaginative strategy right now. The EKAF paper will continue to be discussed. Like it or not, microbicides and PrEP will have a lasting effect on HIV prevention. Patients will be asking for it.


Compliance is the Achilles’ heel of every antiretroviral therapy and non-compliance the main, if not the major factor for developing resistance and treatment failure (Turner 2000). Partial viral suppression with insufficient drug levels is ideal conditions under which resistance grows. There is no doubt – ART must be taken regularly, correctly or not at all. Taking either more than 90% or less than 69% of the treatment are both associated with a lower risk of resistance (Sethi 2003). Compliance is defined as a patient’s consent and acceptance of therapy. In the mid-90s a new term “adherence”, from the English language, was adopted. Since then, the more politically correct term – “adherence” is frequently used. This term refers to both physician and patient working together to set up a treatment concept acceptable to both parties and emphasizes that responsibility for a failure of the therapy is not only the patient’s fault.

Adherence includes all factors that influence staying on a regimen, in terms of acceptability. Whichever term is used, three facts remain:

  1. The success of a treatment is endangered if medication is taken irregularly
  2. Clinicians tend to overestimate a patient’s compliance
  3. Compliance diminishes with the complexity of the treatment

Not only drug consumers, those dependent on alcohol or patients with side effects are considered “risky patients” when it comes to adherence. In several studies, depressed patients, patients living alone and younger patients have been identified as problem groups (Murri 2001, Frank 2002, Glass 2006). Positive factors are the physician’s experience, the patient’s confidence in the positive effects of ART, and social support. Race, sex or stage of disease does not seem to be relevant. The individual’s general view of illness and health, accepting modern medicine and fear of side effects are further considerations. However, all these factors vary greatly, and in the end, adherence is difficult to predict in individual cases (Lerner 1998). The physician must rely on experience and intuition.

The importance of taking drugs regularly has been demonstrated in numerous studies. In one study with 99 patients, in which compliance was evaluated via an electronic monitoring system, the rate of viral treatment failure was only 22% in patients with a compliance level of at least 95% (95% of doses taken). Failure rates of 61% and as much as 80% were measured with a patient’s adherence between 80-94% and < 80% (Paterson 2000). However, it must be taken into consideration that this much-cited study is outdated. Newer drugs, such as darunavir, with longer half-lives, higher resistance barriers and better overall pharmacokinetics may forgive a clearly higher non-compliance (Nelson 2010). In the previously mentioned study, clinicians misjudged their patient’s compliance in 41% of the cases. Nurses did better – judging incorrectly in only 30% of the cases (Paterson 2000). Adherence tended to be overestimated in other studies as well (Miller 2002). The importance of adherence was demonstrated in patients with directly observed therapy (DOT) or directly administered ART (DAART), applied in some penal institutions in the USA. In institutions in Florida, 100% of the patients in a DOT study achieved a viral load below 400 copies/ml after 48 weeks, compared to 81% in an unmonitored control group (Fischl 2001). According to one randomized study, response improved in drug-addicted patients receiving DAART (Altice 2007). More recent data indicate that effects of PI based regimen (given as DAART) are marginal and disappear rapidly as soon as the patient is on his own (Gross 2009).

Poor compliance not only leads to virologic failure. It also bears immunological consequences. In an analysis of two prospective studies, patients with a compliance of 100%, 80-99% and < 79% experienced a reduction in viral load by 2.77, 2.33 and 0.67 logs after a year. At the same time, the CD4 T cell count increased by 179, 159 and 53 cells/µl, respectively (Mannheimer 2002).

Moreover, poor adherence has clinical effects beyond surrogate markers. In a Spanish study, patients who did not take more than 10% of their drugs showed a four-fold increase of mortality risk (Garcia 2002). This data has been confirmed in other studies (Maher 1999, Hogg 2000, Wood 2004). Hospital stays are also less frequent in patients with high adherence to ART (Paterson 2000). In addition, it should be considered that non-adherent patients increase the risk of transmission of primary resistant viruses. The basic mechanisms for development of resistance should be explained to patients. One must emphasize that, in contrast to other chronic illnesses, resistance mutations do not disappear once they have developed. Diabetes and hypertension make effective examples. These diseases may “tolerate” forgetting some tablets occasionally, but HIV is different. Blood glucose and blood pressure levels can easily be lowered again the next day, but with HIV this strategy may not work. Even short-term lapses can have irreversible consequences. And every new occurrence of resistance complicates therapy. Patients have to be made aware of these dangers. Such conversations should be repeated from time to time and become a standard component of routine care. Cooperation with special treatment discussion groups offered by patient-centered support organizations can be useful. The 12-step table below provides additional suggestions. In addition, a number of strategies on improving adherence have been investigated. They range from employment of additional nurses to telephoning patients regularly. This last one, telephone reminders, appears to not have an influence on compliance (Collier 2005).

If adherence remains poor

Despite all efforts, some patients will not succeed in improving their adherence. Physicians and other healthcare providers should not take this personally or feel offended should a patient not want to participate in the advances of medicine. Although it may be difficult to accept the patient’s views on life, disease and treatment, healthcare providers must keep tolerance and acceptance as key components in their interactions with patients. Some providers, especially those who treat selective patient populations in university settings, tend to forget the reality of routine medical practice. Rigidly upholding the principles of modern medicine usually does not help here and putting patients under pressure achieves even less. It is important to clearly outline and explain, advise, help, question and listen.

The question of whether noncompliant patients should continue to be treated with antiretroviral therapy is not always easy to address. On the one hand, there are patients who benefit even from suboptimal therapy; on the other hand, drugs are expensive and should not be prescribed too readily. When resources are limited, available drugs should be distributed with care. Restraint should be applied until the reason for poor compliance is understood.

Twelve steps to improve compliance

  1. Every patient should receive a written (understandable by the patient) treatment plan, which should be reviewed at the end of the visit. It should include a telephone number to call in case of problems or questions, accessible evenings and weekends would be even better.
  2. Patient and clinician should agree on the treatment plan. The patient’s concerns, questions and criticisms should be discussed.
  3. The patient should have the impression that the treatment regimen is not randomly chosen, but tailored to his/her individual needs.
  4. The explanation of a new or modified treatment plan takes time, and should not be rushed – all questions should be answered.
  5. The reasons why adherence is so important should be explained. It makes sense to repeat such conversations – they should not only take place when initiating or modifying treatment, but should be part of routine care.
  6. Possible side effects should be explained, as well as what can be done to alleviate them.
  7. Support groups and other types of assistance should be named and offered.
  8. It is important to tell the patient to come back if any problems are encountered with ART – it is better to try to solve them together than have the patient try to deal with them alone at home.
  9. The patient should know that the treatment regimen must be taken in its entirety (avoid, “Last month I left out the big tablets”).
  10. Prescriptions should be documented, in order to get a rough idea of adherence. Irregularities should be addressed openly. Pills counted, bottles checked?
  11. During all stages of therapy, the patient should be informed of treatment success as seen by reduction of viral load and rise in CD4 count.
  12. Ensure clinical vigilance to detect the early signs of depression and treat appropriately.

Duesbergians – a sect of HIV medicine

Patients who principally refuse antiretroviral treatment form a special case. These patients are frequently under treatment by (shockingly misdirected) doctors, who call themselves “Duesbergians” (after the US virologist and AIDS dissident Peter Duesberg, who denies any association between AIDS and illness). In such cases, it can be very difficult to leave patients to their fate. Informative consultations should be as detailed as possible and preferably documented in writing. Below, an example:

An approximately 40-year-old patient with a long history of untreated HIV, 30 CD4 T cells/µl and cerebral toxoplasmosis (TE), which improved significantly after 4 weeks of acute treatment (the last MRI still showed scattered lesions) introduced his case to the HIV outpatient department. Clinically, he was relatively well and fully oriented and due for discharge that day. In a conversation, the patient categorically refused to start the urgently recommended antiretroviral therapy. His Duesbergian physician had advised him against HIV therapy (“You can die from AZT, and the other drugs are not much better, etc”). He refused antibiotics on principal as well. This was why the patient would not continue the TE maintenance therapy, which had made him suffer from diarrhea (NB, probably cryptosporidiosis), skin problems (seborrhoic dermatitis, thrush), and extreme loss of weight (MAC?) since his first day in hospital. It was very important for him to have a break from all medication.

In such cases, we make sure the patients sign the information sheets. Every patient is allowed to and should decide for himself (if fully cognizant and capable) – they must know and be fully informed about what they are doing. It is important to give the patient control: if they changes their mind, they may return!

In our experience, arguing with medical Duesbergians leads to nothing at all. This sect has a very restricted view of the world and stick to their repetitive –mantra-like arguments. Discussing with them is time consuming and a waste of energy.

Fortunately, these cases have become rarer. The initial widespread scepticism towards ART has decreased significantly, due to its overwhelming success in the last few years. Concerning Peter Duesberg, it has become quiet, at least as far as his HIV activities goes. The sect is in decline.


Antiretroviral treatment is expensive. A health provider needs to be informed about costs for drugs.

In Germany, for example, the price for individual drugs range between €300 (Epivir®) and over €2,400 (Fuzeon®) per month, common threefold therapies range between €14,000 and €24,000 per year. Even within drug classes, there are astonishing differences. Crixivan® (hardly used today) is relatively cheap, while Aptivus® is more than three times the price. Even within primary therapies recommended in guidelines there are great price variations: PIs are almost double the price of NNRTIs in many countries. In Germany, annual costs for Kivexa®+Sustiva® are €6,400 cheaper than for Truvada®+Prezista®/r. If the integraseinhibitor Isentress®, the most expensive drug licensed for primary therapy is used instead of Prezista®,the difference is almost € 8.800 per year. A salvage therapy for a patient with multiresistant virus can amount to as much as €50,000 and more per year. Even though prices alone should not influence the choice of therapy, it is still important for the physician to be aware of the costs.

It is difficult to comprehend the price policy intended by pharmaceutical companies. The reason why prices for directly competing agents (3TC and FTC) are almost exactly the same, whilst prices for other agents of the same drug class differ by 200-300%, cannot be explained by development costs alone. There is no doubt. People are making money with ART and the market is full of competitors – monopolies and patents are being protected.

Despite all the criticism and price discussions, two facts can not be forgotten:

First, the high development costs for new medicines can rise to a billion dollars or more. Most agents never make it to the market. Even a licensed drug such as T-20 may never recoup its development costs. According to Roche, development and research alone chewed up 600 million dollars. To cover such production costs, thousands of patients worldwide would have to be treated with T-20 for several years – a very unrealistic scenario.

Second, there is hardly a more effective therapy than antiretroviral therapy. US estimations assume an expenditure of between $13,000 and $23,000 per additional QALY (quality-adjusted life year) (Freedberg 2001). Compared to many other therapies this is relatively cheap. ART reduces the cost of expensive treatment of opportunistic infections, inpatient and outpatient care. In one German study, between 1997 and 2001 total annual spending per patient decreased from €35,865 to €24,482 (Stoll 2002). Many patients return to work, resulting in an overall economic gain for society (Sendi 1999).

Nevertheless, ART is expensive. Therefore, it should be expected from patients to use up remaining packets of drugs, etc. if the reasons for a change in therapy are not urgent. Concerns of pill reduction or doubts about long-term toxicity should be part of an ongoing discussion with patients. All patients need to be made aware of the costs of medication –to make them aware of the value of the therapy.

Initially, ART should be prescribed for a month. This way, mountains of unused pills will not be wasted, if signs of intolerability or complicated adverse events set in. If response to ART is positive and its effects constant, prescriptions can then be done for a period of three months.

Many companies now offer three-month supply packages. This practice has not been without criticism. In any case, prescriptions of longer than a three months supply should be avoided.

In the future, we all need to be more aware of the costs for ART. The patents for AZT, ddI, 3TC, d4T and abacavir, but also saquinavir will disappear or have already gone. Efavirenz and nevirapine will soon follow. It will be interesting to watch price developments when generics come to the market, as they have in resource-limited settings


Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010, 329:1168-74.

Altice FL, Maru DS, Bruce RD, et al. Superiority of directly administered antiretroviral therapy over self-administered therapy among HIV-infected drug users: a prospective, randomized, controlled trial. CID 2007;45:770-8.

Attia S, Egger M, Müller M, Zwahlen M, Low N. Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis. AIDS. 2009 Apr 17.

Auvert B, Taljaard D, Lagarde E, et al. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2005; 2: 298.

Baeten JM, Lingappa J, Beck I, et al. Herpes simplex virus type 2 suppressive therapy with acyclovir or valacyclovir does not select for specific HIV-1 resistance in HIV-1/HSV-2 dually infected persons. J Infect Dis 2011, 203:117-21.

Baeten JM, Strick LB, Lucchetti A, et al. Herpes simplex virus (HSV)-suppressive therapy decreases plasma and genital HIV-1 levels in HSV-2/HIV-1 coinfected women: a randomized, placebo-controlled, cross-over trial. J Infect Dis 2008, 198:1804-8.

Bailey RC, Moses S, Parker CB, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomized controlled trial. Lancet 2007;369:643-56.

Barreiro P, del Romero J, Leal M, et al. Natural pregnancies in HIV-serodiscordant couples receiving successful antiretroviral therapy. J AIDS 2006;43:324-6.

Blower SM, Aschenbach AN, Gershengorn HB, Kahn JO. Predicting the unpredictable: transmission of drug-resistant HIV. Nat Med 2001, 7:1016-20.

Castilla J, Del Romero J, Hernando V, Marincovich B, Garcia S, Rodriguez C. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr 2005; 40: 96-101.

Celum C, Wald A, Hughes J, et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomized, double-blind, placebo-controlled trial. Lancet 2008, 371:2109-19.

Celum C, Wald A, Lingappa JR, et al. Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2. NEJM 2010, 362:427-39.

Cohen J. Cambodian leader throws novel prevention trial into limbo. Science 2004, 305:1092.

Cohen J. Treat Everyone Now? A ‘Radical’ Model to Stop HIV’s Spread. Science. 2008;322:1453.

Collier AC, Ribaudo H, Mukherjee AL, et al. A randomized study of serial telephone call support to increase adherence and thereby improve virologic outcome in persons initiating antiretroviral therapy. J Infect Dis 2005, 192:1398-406.

Crepaz N, Hart TA, Marks G. Highly active antiretroviral therapy and sexual risk behavior: a meta-analytic review. JAMA 2004, 292:224-36.

Cu-Uvin S, Caliendo AM, Reinert S, et al. Effect of HAART on cervicovaginal HIV-1 RNA. AIDS 2000, 14: 415-21.

De Cock KM , Gilks CF, Lo YR, et al. Can antiretroviral therapy eliminate HIV transmission? Lancet. 2008. Nov 25.

Delany S, Mlaba N, Clayton T, et al.  Impact of aciclovir on genital and plasma HIV-1 RNA in HSV-2/HIV-1 co-infected women: a randomized placebo-controlled trial in South Africa. AIDS 2009, 23:461-9.

Desquilbet L, Deveau C, Goujard C, et al. Increase in at-risk sexual behaviour among HIV-1-infected patients followed in the French PRIMO cohort. AIDS 2002, 16:2329-33.

Desrosiers R. Scientific obstacles to an effective HIV vaccine. Abstract 91, 15th CROI 2008, Boston.

Dunne EF, Whitehead S, Sternberg M, et al. Suppressive acyclovir therapy reduces HIV cervicovaginal shedding in HIVand HSV-2-infected women, Chiang Rai, Thailand. J AIDS 2008, 49:77–83.

Fiore JR, Suligoi B, Saracino A, et al. Correlates of HIV-1 shedding in cervicovaginal secretions and effects of antiretroviral therapies. AIDS 2003;17:2169-76.

Fischl M, Castro J, Monroig R, et al. Impact of directly observed therapy on long-term outcomes in HIV clinical trials. Abstract 528, 8th CROI 2001, Chicago, USA.

Frank I. Once-daily HAART: toward a new treatment paradigm. J AAIDS 2002, 31 Suppl 1:S10-5, discussion S24-5. Review.

Freedberg KA, Losina E, Weinstein MC, et al. The cost effectiveness of combination antiretroviral therapy for HIV disease. N Engl J Med 2001;344:824-31.

Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS 2006;20:73-83.

Friedland GH, Williams A. Attaining higher goals in HIV treatment: the central importance of adherence. AIDS 1999, 13 Suppl 1: S61-72.

Garcia de Olalla P, Knobel H, Carmona A, et al. Impact of adherence and HAART on survival in HIV-infected patients. J AIDS 2002, 30:105-10.

Garcia-Lerma JG, Otten RA, Qari SH, et al. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med 2008;5:

Garnett GP , Baggaley RF. Treating our way out of the HIV pandemic: could we, would we, should we? Lancet. 2008. Nov 25.

Glass TR, De Geest S, Weber R, et al. Correlates of Self-Reported Nonadherence to Antiretroviral Therapy in HIV-Infected Patients: The Swiss HIV Cohort Study. J AIDS 2006, 41:385-392.

Granich RM , Gilks CF, Dye C, et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2008. Nov 25.

Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010, 363:2587-99.

Gray R, Kigozi G, Serwadda D, et al. Randomized trial of male circumcision for HIV prevention in Rakai, Uganda, Abstract 155LB, 14th CROI 2007, Los Angeles.

Gray RH, Serwadda D, Tobian AA, et al. Effects of genital ulcer disease and herpes simplex virus type 2 on the efficacy of male circumcision for HIV prevention: Analyses from the Rakai trials. PLoS Med 2009, 6:e1000187.

Gross R, Tierney C, Andrade A, et. Modified directly observed antiretroviral therapy compared with self-administered therapy in treatment-naive HIV-1-infected patients: a randomized trial. Arch Intern Med 2009, 169:1224-32.

Hogg R, Yip B, Chan K. Non-adherence to triple combination therapy is predictive of AIDS progression and death in HIV-positive men and women. Abstract TuOrB419, 13th International AIDS Conference 2000, Durban, South Africa.

Hosseinipour M, Cohen MS, Vernazza PL, Kashuba AD. Can antiretroviral therapy be used to prevent sexual transmission of HIV type 1? Clin Infect Dis 2002, 34:1391-5.

Kaul R, Kimani J, Nagelkerke NJ, et al. Monthly antibiotic chemoprophylaxis and incidence of sexually transmitted infections and HIV-1 infection in Kenyan sex workers: a randomized controlled trial. JAMA 2004;291:2555-62.

Kwara A, Delong A, Rezk N, et al. Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. Clin Infect Dis 2008;46:719-25.

Lampinen TM, Critchlow CW, Kuypers JM, et al. Association of antiretroviral therapy with detection of HIV-1 RNA and DNA in the anorectal mucosa of homosexual men. AIDS 2000;14:

Law MG, Prestage G, Grulich A, Van de Ven P, Kippax S. Modelling the effect of combination antiretroviral treatment on HIV incidence. AIDS 2001, 15:1287-94.

LeGoff J, Weiss HA, Gresenguet G, et al. Cervicovaginal HIV-1 and herpes simplex virus type 2 shedding during genital ulcer disease episodes. AIDS 2007;21:1569-78.

Lerner BH, Gulick RM, Dubler NN. Rethinking nonadherence: historical perspectives on triple-drug therapy for HIV disease. Ann Intern Med 1998, 129:573-8.

Lie RK, Emanuel EJ, Grady C. Circumcision and HIV prevention research: an ethical analysis. Lancet 2006; 368: 522-5.

Lingappa JR, Baeten JM, Wald A, et al. Daily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial. Lancet 2010, 375:824-33.

Liu A, Vittinghoff E, Irby R, et al. BMD Loss in HIV– Men Participating in a TDF PrEP Clinical Trial in San Francisco. Abstract 93, 18th CROI 2011, Boston.

Liuzzi G, Chirianni A, Bagnarelli P, Clementi M, Piazza M. A combination of nucleoside analogues and a protease inhibitor reduces HIV-1 RNA levels in semen: implications for sexual transmission of HIV infection. Antivir Ther.1999, 4:95-9.

Maher K, Klimas N, Fletcher MA. Disease progression, adherence, and response to protease inhibitor therapy for HIV infection in an Urban Veterans Affairs Medical Center. J Acquir Immune Defic Syndr 1999,  22:358-63.

Mannheimer S, Friedland G, Matts J, et al. The consistency of adherence to antiretroviral therapy predicts biologic outcomes for HIV-infected persons in clinical trials. Clin Infect Dis 2002, 34: 1115-21.

Marcelin AG, Tubiana R, Lambert-Niclot S, et al, and the Pitie-Salpetriere AMP a Risque Viral Study Group. Detection of HIV-1 RNA in seminal plasma samples from treated patients with undetectable HIV-1 RNA in blood plasma. Abstract 51, 16th CROI 2009 Montréal.

McCormack S, Ramjee G, Kamali A, et al. PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial. Lancet 2010, 376:1329-37.

Mertenskötter T, Kaptur PE. Update on microbicide research and development – seeking new HIV prevention tools for woman. Eur J Med Res 2011, 16:1-6.

Miller LG, Liu H, Hays RD, et al. How well do clinicians estimate patients´ adherence to combination antiretroviral therapy? J Gen Intern Med 2002; 17: 1-11.

Millett GA, Flores SA, Marks G, Reed JB, Herbst JH. Circumcision status and risk of HIV and sexually transmitted infections among men who have sex with men: a meta-analysis. JAMA 2008, 300:1674-84.

Mills E, Cooper C, Anema A, Guyatt G. Male circumcision for the prevention of heterosexually acquired HIV infection: a meta-analysis of randomized trials involving 11,050 men. HIV Med 2008, 9:332-5. Review.

Montaner JS, Hogg R, Wood E, Kerr T, Tyndall M, Levy AR, Harrigan PR. The case for expanding access to highly active antiretroviral therapy to curb the growth of the HIV epidemic. Lancet 2006, 368:531-536.

Morin SF, Shade SB, Steward WT, et al. A behavioral intervention reduces HIV transmission risk by promoting sustained serosorting practices among HIV-infected men who have sex with men. J AIDS 2008, 49:544-51.

Mulligan K, Glidden D, Gonzales P, et a l. Effects of FTC/TDF on bone mineral density in seronegative men from 4 continents: DEXA results of the Global iPrEx Study. Abstract 94LB, 18th CROI 2011, Boston.

Murri R, Ammassari A, De Luca A, et al. Self-reported nonadherence with antiretroviral drugs predicts persistent condition. HIV Clin Trials 2001, 2:323-9.

Nagot N, Ouedraogo A, Foulongne V, et al. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. NEJM 2007;356:790-9.

Nathanson N. AIDS vaccine at the crossroads. Abstract 92, 15th CROI 2008, Boston.

Neely MN, Benning L, Xu J, et al. Cervical shedding of HIV-1 RNA among women with low levels of viremia while receiving highly active antiretroviral therapy. J AIDS 2007;44:38-42.

Nelson M, Girard PM, Demasi R, et al. Suboptimal adherence to darunavir/ritonavir has minimal effect on efficacy compared with lopinavir/ritonavir in treatment-naive, HIV-infected patients: 96 week ARTEMIS data. J Antimicrob Chemother 2010, 65:1505-9.

Nunnari G, Otero M, Dornadula G, et al. Residual HIV-1 disease in seminal cells of HIV-1-infected men on suppressive HAART: latency without on-going cellular infections. AIDS 2002;16:39-45.

Padian NS, van der Straten A, Ramjee G, et al. Diaphragm and lubricant gel for prevention of HIV acquisition in southern African women: a randomized controlled trial. Lancet 2007;370:251-61.

Paterson DL, Swindells S, Mohr J. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000, 133:21-30.

Paz-Bailey G, Sternberg M, Puren AJ, et al. Improvement in healing and reduction in HIV shedding with episodic acyclovir therapy as part of syndromic management among men: a randomized, controlled trial. J Infect Dis 2009, 200:1039-49.

Porco TC, Martin JN, Page-Shafer KA, et al. Decline in HIV infectivity following the introduction of HAART. AIDS 2004, 18:81-8.

Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of HIV type 1. N Engl J Med 2000, 342:9219.

Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009, 361:2209-20.

Sánchez J, Sal Y Rosas VG, Hughes JP, et al. Male circumcision and risk of HIV acquisition among MSM. AIDS 2011, 25:519-23.

Schwarze S. Getretener Quark wird breit, nicht stark: Was man von den “AIDS-Skeptikern” wirklich lernen kann.

Schwebke JR. Abnormal vaginal flora as a biological risk factor for acquisition of HIV infection and sexually transmitted diseases. J Infect Dis 2005, 192:1315-7.

Sendi PP, Bucher HC, Harr T, et al. Cost effectiveness of HAART in HIV-infected patients. Swiss HIV Cohort Study. AIDS 1999, 13:1115-22.

Serwadda D, Wawer MJ, Makumbi F, et al. Circumcision of HIV-infected men: effects on high-risk human papillomavirus infections in a randomized trial in Rakai, Uganda. J Infect Dis 2010, 201:1463-9.

Sethi AK, Celentano DD, Gange SJ, Moore RD, Gallant JE. Association between adherence to antiretroviral therapy and HIV drug resistance. Clin Infect Dis 2003;37:1112-8.

Sheth P, Kovacs C, Kemal K, et al, and the Toronto Mucosal HIV Res Group. Persistent HIV RNA shedding in semen despite effective ART. Abstract 50, 16th CROI 2009 Montréal.

Siegfried N, Muller M, Deeks J, et al. HIV and male circumcision–a systematic review with assessment of the quality of studies. Lancet Infect Dis 2005; 5: 165-73.

Singh JA, Mills EJ. The abandoned trials of pre-exposure prophylaxis for HIV: what went wrong? PLoS Med 2005, 2:e234.

Stoll M, Claes C, Schulte E, et al. Direct costs for the treatment of HIV-infection in a German cohort after the introduction of HAART. Eur J Med Res 2002, 7:463-471

Stone A, Jiang S. Microbicides: stopping HIV at the gate. Lancet 2006; 368: 431-3.

Stürmer M, Doerr HW, Berger A, Gute P. Is transmission of HIV-1 in non-viraemic serodiscordant couples possible? Antivir Ther 2008, 13:729-32.

Tobian A, Serwadda D, Quinn T, et al. Trial of male circumcision: prevention of HSV-2 in men and vaginal infections in female partners, Rakai, Uganda. Abstract 28LB, 15th CROI 2008, Boston.

Tovanabutra S, Robison V, Wongtrakul J, et al. Male viral load and heterosexual transmission of HIV-1 subtype E in northern Thailand. J Acquir Immune Defic Syndr. 2002. 29:275-83.

Turner BJ. Adherence to antiretroviral therapy by HIV-infected patients. J Infect Dis 2002; 185 Suppl 2: S143-51.

Van Damme L, Govinden R, Mirembe FM, et al. Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med 2008, 359:463-72.

Van Damme L, Ramjee G, Alary M, et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomized controlled trial. Lancet 2002; 360: 971-7.

Van de Perre P, Segondy M, Foulongne V, et al. Herpes simplex virus and HIV-1: deciphering viral synergy. Lancet Infect Dis 2008, 8:490-7.

Vanpouille C, Lisco A, Derudas M, et al. A new class of dual-targeted antivirals: monophosphorylated acyclovir prodrug derivatives suppress both human immunodeficiency virus type 1 and herpes simplex virus type 2. J Infect Dis 2010, 201:635-43.

Velasco-Hernandez JX, Gershengorn HB, Blower SM. Could widespread use of combination antiretroviral therapy eradicate HIV epidemics? Lancet Infect Dis 2002, 2:487-93.

Vernazza PL, Troiani L, Flepp MJ, et al. Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV. The Swiss HIV Cohort Study. AIDS 2000;14:117-21.

Vettore MV, Schechter M, Melo MF, Boechat LJ, Barroso PF. Genital HIV-1 viral load is correlated with blood plasma HIV-1 viral load in Brazilian women and is reduced by antiretroviral therapy. J Infect 2006;52:290-3.

Watson-Jones D, Wald A, Celum C, et al. Use of acyclovir for suppression of human immunodeficiency virus infection is not associated with genotypic evidence of herpes simplex virus type 2 resistance to acyclovir: analysis of specimens from three phase III trials. J Clin Microbiol 2010, 48:3496-503.

Watson-Jones D, Weiss HA, Rusizoka M, et al. Effect of herpes simplex suppression on incidence of HIV among women in tanzania. N Engl J Med 2008, 358:1560-71.

Wawer M, Kigozi G, Serwadda D, et al. Trial of male circumcision in hiv+ men, rakai, uganda: effects in HIV+ men and in women partners. Abstract 33LB, 15th CROI 2008, Boston.

Weiss HA, Thomas SL, Munabi SK, Hayes RJ. Male circumcision and risk of syphilis, chancroid, and genital herpes: a systematic review and meta-analysis. Sex Transm Infect 2006; 82: 101-9

Williams BG, Lloyd-Smith JO, Gouws E, et al. The potential impact of male circumcision on HIV in Sub-Saharan Africa. PLoS Med 2006; 3:

Wilson DP, Law MG, Grulich AE, et al. Relation between HIV viral load and infectiousness: a model-based analysis. Lancet 2008, 372:314-20.

Wood E, Hogg RS, Yip B, et al. The impact of adherence on CD4 cell count responses among HIV-infected patients. J Acquir Immune Defic Syndr 2004, 35:261-8.

Yang O, Daar E, Jamieson B, et al. HIV-1 Clade B superinfection: evidence for differential immune containment of distinct clade b strains. J Virol 2005; 79:860-8

Zuckerman RA, Lucchetti A, Whittington WL, et al. Herpes simplex virus (HSV) suppression with valacyclovir reduces rectal and blood plasma HIV-1 levels in HIV-1/HSV-2-seropositive men: a randomized, double-blind, placebo-controlled crossover trial. J Infect Dis 2007, 196: 1500–8.

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Filed under 6.12. Prevention, compliance, costs, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy

6.13. Global Access to HIV Treatment

– Rob Camp –

We all know this data, and we gloss over it every time we go to an international meeting:

•  Some 7,000 people become infected with HIV every day.

•  Approximately 5.25 million people are currently receiving ART, while at least 14.6 million people are still in need.

•  For every 2 people put on treatment, 5 more become infected.

•  With universal access, approximately 6.7 million people would receive life-saving ART, 2.6 million new infections could be averted and 1.3 million lives saved. Based on global goals and targets for 2015, it is estimated that an investment of US$25.1 billion/yr will be required for the global AIDS response in low- and middle-income countries (, accessed 19.04.10).

In the developing world, the price of ART has fallen drastically in recent years. Even so their cost remains an obstacle to access for many millions. Moreover, the health infrastructure required to deliver ART and maintain adherence is lacking in many places. Access to drugs depends not only on financial and human resources. It depends also on people being aware of their HIV status, knowledgeable about treatment, and empowered to seek it. Thus public information and education are important elements in widening access, alongside efforts to build or strengthen health services. Stigma has been and remains a major stumbling block in wanting, seeking and taking the treatment regimen correctly. The campaign for universal access to life-saving drugs for HIV and AIDS, started originally by grassroots AIDS activists, is today a major focus of attention of UN agencies and other influential organizations at national and global levels.

The Declaration of Commitment on HIV/AIDS, unanimously endorsed by the UN General Assembly in 2001, embraced equitable access to care and treatment as a fundamental component of a comprehensive and effective global HIV response. Since then many countries, through the support of intergovernmental organizations and donors, have definitively demonstrated the ability to deliver HIV treatment in very resource-limited settings. Access to treatment has helped mobilize communities in response to HIV, preserved the health and viability of households vulnerable to HIV, and strengthened HIV prevention efforts in many parts of the world.

In the goal to reach universal access to HIV prevention, treatment, care and support, leadership at national level is required to establish policies that support treatment scale-up by:

•  increasing the number of people who choose to know their HIV status;

•  reducing HIV stigma;

• building human capacity to sustain treatment through training and better use of current human resources;

• improving supply management and integrating HIV care with other health services.

In 2011, the international community recommitted to the goal of universal access. This time, countries committed to achieving universal access by 2015. The goal of universal access is also part of Millennium Development Goal (MDG) 6 which includes the goal of halting and beginning to reverse the spread of HIV/AIDS by 2015.

The updated 2011-2015 global health strategy was released in June 2011. This strategy outlines four key targets that countries need to achieve if universal access and MDG 6 are to be realised: reduce new infections by 50 percent among young people (15-24 years), reduce TB-related mortality by 50 percent, eliminate new infections in children, and reduce HIV-related mortality.

Major Players


The President’s Emergency Plan for AIDS Relief (PEPFAR) was launched in 2003 to combat global HIV/AIDS, and is the largest commitment by any nation to combat a single disease in history. During PEPFAR’s initial phase covering 2004-2008, the United States invested nearly $19 billion in PEPFAR (defined to include bilateral HIV/AIDS and tuberculosis programs, as well as contributions to the Global Fund to Fight AIDS, Tuberculosis and Malaria). For FY 2011, $5.56 billion was enacted for bilateral HIV/AIDS programs, $1.05 billion for the Global Fund; the line item for bilateral TB programs has not been agreed upon yet.

PEPFAR and the fight against HIV/AIDS is now the cornerstone of the US Global Health Initiative, which commits $63 billion over six years to support countries in improving and expanding access to health services. As part of the Global Health Initiative, PEPFAR is moving from its initial emergency focus to a heightened emphasis on sustainability, and serves as a platform for expanded responses to a broad range of global health needs. Through its partnerships with 31 countries, as of September 2010, PEPFAR directly supported ART for over 3.2 million men, women and children. PEPFAR partnerships have directly supported care for nearly 11 million people affected by HIV/AIDS.

In 2010, PEPFAR directly supported prevention of mother-to-child transmission programs that allowed nearly 100,000 infants of HIV-infected mothers to be born without HIV, adding to the nearly 340,000 infants born without HIV due to PEPFAR support during 2004-2009. This of course, is not the limit as it is estimated that less than 25% of pregnant HIV-infected women get the care they need (beyond point-of-care transmission prevention). In FY 2010, PEPFAR also directly supported HIV counseling and testing for nearly 33 million people, providing what may be an important entry point to prevention, treatment, and care.

2004 – 2011 PEPFAR Funding ($ in USD millions)










Bilateral HIV/AIDS Programs1




















Bilateral TB Prog’s










TOTAL PEPFAR (w/o malaria)










1 Bilateral HIV/AIDS Programs includes funding for bilateral country/regional programs, UNAIDS, IAVI, Microbicides and NIH HIV/AIDS research.
*Possibly not the final total. For final US spending on PEPFAR 2012, please see Fiscal Year 2012 Budget Tracker at
Note: All funding amounts have been rounded to the nearest million $ so the numbers shown in the table may not sum to the totals.


The Global Fund to Fight AIDS, Tuberculosis and Malaria is an international financing institution that invests the world’s money to save lives. To date, it has committed US$ 22.4 billion in 150 countries to support large-scale prevention, treatment and care programs against the three diseases. Round 11 of the grants cycle is now open until 15 Dec 2011. Right now, however, the Fund is unable to provide any accurate forecast or give assurances regarding the level of resources that will actually be available, since very few pledges have been confirmed.

The actual amount available will be influenced by three key considerations: 1) the level and timing of donor pledges, 2) new pledges to be announced at the time of the mid-term replenishment review in March 2012 and 3) the extent of any savings that the Global Fund will achieve through the stringent application of “value for money” and new performance-based funding principles, which can be seen at

“More donor assistance is urgently needed to close the financing gap in health in the poorest countries of the world… Assistance from developed nations should increase from the current levels of about US$ 6 billion per year globally to US$ 27 billion by 2007 and US$ 38 billion by 2015”, according to the Commission on Macroeconomics and Health, 2003. As can be seen from the chart above, if PEPFAR represents 50% of the Global total, we are far from the target, about 1/3 of where we need to be.

The Global Fund is meant to constitute a major source of this funding. To operate effectively, the Global Fund requires strong and consistent financial commitments from all of its stakeholders. It is thus essential that substantial new pledges are received to finance additional grants and to continue successful programs.

Pledges and contributions from donors are received on an ad-hoc voluntary basis (, accessed 24.05.10). The Global Fund is relatively transparent and has an architecture of application, funding structure, management of performance and future planning that is inclusive and as broad-based as a top-down organism from Geneva that disburses money locally can be ( That much being said, the Fund often has to deal with scandals that stop funding from any one or group of countries temporarily. In 2011, we saw this happen with some European countries in what was a fairly small local abuse of funds report (Germany, Sweden and the Netherlands have all re-committed after temporary halts). For other reasons, like the economic downturn that started in 2008 and that shows little sign of abating in many places, Spain and Italy have not contributed the Global Fund for 2011 as of 8 September, which leaves a funding gap of close to half a billion euros. Other European countries with less commitments (Portugal, Ireland, Switzerland) have also not contributed this year.

The World Bank

The World Bank supplies more than just money for drugs – large chunks of its investment is intended for infrastructure of health systems (i.e., child health, health system performance, etc). This money, at least that specifically under AIDS, started to fall in 2004. Although the single year with most money was 2007, it did little to change the overall 3-year rolling average of being half now what it was 6 years ago. The 2010 moneys are at about the 1996 investment level. Which does not mean that infrastructure money may not be coming in under other themes – like malaria, nutrition or tuberculosis (, accessed on 20.05.10). They also lend, offer technical support and analytic work. For example, in light of the current economic crisis, the Bank is supporting countries through technical assistance and collaborative efforts for a joint response by assessing the fiscal implications of scaling up national AIDS programs in Botswana, South Africa, Uganda and Swaziland. They lent some $55 million to African HIV programs in 2010, and expect to lend some $90 million in 2011.


UNAIDS provides technical support to countries to assist them with expertise and planning for their national AIDS programs, to help ‘make the money work’ for the people on the ground, those that need it most. UNAIDS tracks, evaluates and projects the financial resource requirements at global, regional and country levels to generate reliable and timely information on the epidemic and the response. Based on these evaluations, UNAIDS produces guidelines and progress reports. Much of the international data we juggle is set and approved by UNAIDS. At the 2011 IAS meeting in Rome, they set out a plan of how to move forward in middle- to low-income countries in the face of the current economic downturn. The total investment needs should be met by a combination of sources, each of which has the potential to increase: The first is domestic public investment within low and middle-income countries, which can increase as a result of economic growth in those countries, as well as an increase in the historically relatively low level of priorisation to the AIDS response in their domestic budget. This, while a great idea, is not something that can be “turned on” overnight and while the lobbying for this goes on, people need treatment. A second source is to promote the potential for private financing and philanthropic foundations in low and middle-income countries. A third source would be an increase in the level of donor financing, compatible with a movement in the direction of meeting the target of devoting 0.7% of GDP in OECD countries to development assistance. Needed: Low- to middle-income countries’ domestic health budgets have to average at least 15% of government revenue (as in the Abuja Declaration in Africa). Another promising approach would be to expand innovative mechanisms like indirect taxation (airline tickets, mobile phone usage, exchange rate transactions) to support global health initiatives, and ensure that HIV benefits from these in relation to disease burden. The larger community must continue to support and strengthen existing financial mechanisms, including the Global Fund and relevant UN organizations.

The Bill and Melinda Gates Foundation

The largest private philanthropic organization to date is located in Seattle, US, “focusing on improving people’s health and giving them the chance” to emerge from “hunger and extreme poverty.” They have approximately 957 employees with an endowment of USD 36.3 billion. They have committed USD 25.364 billion since inception and in 2010 committed grants to the tune of USD 2.6 billion in over 100 countries. Much of these moneys are for non-AIDS-specific works, including development (reducing poverty and hunger). In health, they fight and prevent enteric and diarrheal diseases, HIV/AIDS, malaria, pneumonia, TB, neglected and infectious diseases, working on integrated heath solutions, improving delivery of existing tools and supporting research and development in new interventions like vaccines, drugs and diagnostics ( They have supported the Global Fund with some $650 million as of mid-2010.

Drugs available from whom and where

FDA’s qualification of generics

Generic drugs are important options that allow greater access to health care. Generic drugs approved by FDA have the same high quality, strength, purity and stability as brand-name drugs. And, the generic manufacturing, packaging, and testing sites must pass the same quality standards as those of brand name drugs.

For PEPFAR use, all drugs need FDA approval. As of 2 September 2011, FDA had approved some 132 generic drugs for use in the PEPFAR program that are approved in as short a time as two to six weeks. While quality, strength, purity and stability are guaranteed, administration, delivery and correct use is another issue. For example, a drug approved in May 2010 was a fixed-dose combination of d4T and 3TC. And there the rub. Generics companies (in the case of FDA for PEPFAR, to date there are eleven Indian generics companies, 1 South African company, one company from China and one from the US) copy what is easiest and cheap, not necessarily the most innovative or optimal treatments only. We must continue to try to remind the generics companies that what is best for the patient will continue selling for years, while (hopefully) a less-than-optimal combination like 3TC+d4T has a limited life-time, and can do a lot of harm via side effects along the way.

Lopinavir/r is the first PI approved for generic licensing although there are eight approved PIs on the market in the Global North. Aurobindo got approval for a 25 mg version of ritonavir in early 2009, what could be a very interesting option in boosting in the future. Matrix got an FDA approval of a ritonavir 50 mg version (with lopinavir) on the same day. Matrix and Emcure both have approval for atazanavir (2010).

There are a handful of generics companies with an abacavir approval. As HLA testing for abacavir HSR is not easily available in the Global South, it is very important to train both the medical profession as well as users on diagnosis of HSR and what to do if it occurs, and the importance of never re-starting it once HSR is suspected, things that from an international regulatory agency would be hard to monitor. And although REMS programs from FDA or EMA would accept information on side effects from the Global South (which has up to 5 times the amount of people on drug), they probably contribute little to the overall numbers and thus better definition of safety of these drugs.

In 2011 (until 18 August), FDA has issued one warning letter to one generics company that manufactures HIV products. The letter was unclear about if it was related to an HIV product or not.

In total, in 2011, 400 FDA inspectors will perform more than 2,200 drug-related inspections. FDA takes many different enforcement actions.

WHO-approved generics

Prequalification and quality assurance of antiretroviral products – a fundamental human right

WHO’s Prequalification Programme conducts evaluation and inspection activities and builds national capacity for manufacturing and monitoring high-quality medicines. WHO began reviewing HIV antiretroviral drugs for prequalification in 2001.

In 2005–2006, WHO conducted a quality assurance survey of antiretroviral medicines in Cameroon, the Democratic Republic of the Congo, Kenya, Nigeria, Uganda, United Republic of Tanzania and Zambia. Of the 395 samples tested, none had quality deficiencies that would pose a risk to the people taking them. The results of this and future surveys on drug quality are key to ensuring that the pace of scaling up treatment does not compromise the quality of the medicines available.

Invitations to manufacturers to submit an expression of interest (EOI) for product evaluation are issued not only for HIV/AIDS-related care and treatment products, but also for antimalarial medicines, antituberculosis medicines, influenza-specific antiviral medicines and reproductive health products.

On the WHO List of Prequalified Medicinal Products is an extended list of 290 products (, accessed 9.09.2011) for HIV/AIDS, made by both originator companies and generics companies. Prequalification may be better described as pre-, on-going, and post-qualification, as they do inspections at all these time points. On this list is atazanavir, which has WHO approval from a BMS manufacturing facility in the US as well as an Indian generics company. Neither Brazil nor Thailand have pre-approved drugs on either list (FDA or WHO) because although they both have and produce generic HIV drugs, they do so only for domestic use.

On the list are many drugs for OIs (acyclovir, ceftriaxone, ciprofloxacin, amongst others). WHO also approves medicines quality control laboratories (QCLs): 21 QCLs are currently prequalified all around the world.

Antiretroviral therapy in low- and middle-income countries by region, December 2009


Estimated number of people receiving ART

Estimated number of people needing ART

ART coverage

Sub-Saharan Africa

3 911 000

10 600 000


Eastern and southern Africa

3 203 000

7 700 000


West and central Africa

709 000

2 900 000


Latin America and the Caribbean

478 000

950 000


Latin America

425 000

840 000


The Caribbean

52 400

110 000


East, South and South-East Asia

739 000

2 400 000


Europe and Central Asia

114 000

610 000


North Africa and the Middle East

12 000

100 000



5 254 000

14 600 000


Source: Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Progress report 2010 (WHO, UNICEF, UNAIDS), p.53.

With the new threshold of starting treatment at 350 CD4s, even with more people starting treatment, the percentage of those treated who should be on treatment has actually fallen.

A chasm

Improved treatment in line with scientific evidence and recognized international standards of care

Médecins Sans Frontières (MSF, Doctors without Borders) serves approximately 210,000 of the ~5 million people today on treatment, and because they are on the front lines in clinics and health centers in more than 70 countries, their advocacy is not of the ivory tower type. Due to the implementation of ART, they have seen first hand the reduction in mortality for both adults and children, the lowering of incidence of TB as well as the importance of supporting HIV prevention by lowering incidence. They believe that not continuing to invest today in improved treatment and protocols will cost lives down the road, increase a double standard in HIV care and lead to increased costs later. They believe that there is a clear risk that donors may not continue to support or try to delay the implementation of proven and recommended medical strategies for the sake of short-term savings. They recommend:

• Supporting initiation of ART at a CD4 T cell threshold of 350/μl to reduce the incidence of TB and other OIs and improve survival rates, reducing the need for costly and complex acute care.

• Implementing a tenofovir-based first-line regimen will allow patients to stay on their first regimen as long as possible with fewer side effects and delay the need for more costly second-line regimens.

• Providing access to viral load testing to support adherence and detect treatment failure earlier, thereby preventing resistance and needless switching to expensive sub-optimal second-line treatment.

• Supporting innovation that can lead to further improvement and simplification of HIV treatment in resource-poor settings.

According to MSF, most people with HIV/AIDS in need of treatment in the world will die within three years if they do not gain access to treatment now.

How to ensure that prices of drugs and diagnostics remain reasonable?

The international community needs to support policies that will enable funds to stretch as far as possible to meet needs and contain costs in the short- and long-term by ensuring a competitive supply for drugs.

In accordance with the Doha Declaration on TRIPS and Public Health, governments can authorize governmental use or compulsory licenses to ensure generic production of patented products (as in Brazil and Thailand).

Companies and governments can support the Medicines Patent Pool for antiretroviral medicines that originated at UNITAID (, now a freestanding organization at This mechanism brings together patents held by different owners and makes them available to others for generic production and further development. MSF has started a ‘Make It Happen Campaign”. Gilead was the first company to sign on, in July 2011. They are currently negotiating with F. Hoffmann-La Roche, Sequoia Pharmaceuticals, the US National Institutes of Health and ViiV Healthcare. BI and BMS have just started to negotiate. This Pool could save lower income countries more than $1 billion a year in drug costs.

Prices of first-line regimens in low-income countries

The median price paid for tenofovir+3TC+efavirenz (prequalified by WHO) in low-income countries in June 2011 ranged from US$ 143 per person per year for the two pill dose to US$ 173 for the fixed-dose combination. The weighted average median price of the four combinations most widely used in first-line treatment (representing 86% of the prescribed first-line treatments in low-income countries) was US$ 170 per person per year in 2007. The decline in drug prices between 2004 and 2007 can be attributed to the scaling up of treatment programs, increased competition between a growing number of products prequalified by WHO, new pricing policies by pharmaceutical companies and successful negotiations between the William J. Clinton Foundation (CHAI) and major generic manufacturers. While combinations with d4T are cheaper, and studies continue to be carried out with even-lower doses, etc, the long-term side effects do not outweigh the harm, and programs should move to tenofovir-containing regimens as soon as they can.

Second-line regimens

Second-line regimens are still significantly more expensive than first-line regimens in low- and middle-income countries. In 2011, the median cost of a regimen of AZT/3TC+atazanavir/r, a newly indicated second-line regimen, was US$ 442 in low-income countries and up to six times that in middle-income countries. The actual prices paid for second-line regimens vary significantly between countries. For example, South Africa pays an average price of US$ 1,600 per person per year for ddI+abacavir+lopinavir/r, whereas El Salvador paid US$ 3,448 per person per year for the same regimen in 2007.

In the UK, a recent study showed that first-line treatments can last 8 years or longer, but by then, of those who start, more than 25% of people will have failed (UK Chic 2010). If ARV access started in earnest in 2002, we are at the 8-year mark. What to do with the approximately 1 million people who must need to move to a new regimen? And of the regimens that fail, NNRTIs fail at a rate almost three times higher than the rate of PIs. Most people in resource-limited settings are on an NNRTI containing regimen. MSF estimates that regimen failure is “largely under-diagnosed” due to limited lab facilities for viral load testing, which can only lead to resistance and harder-to-construct post-first-line regimens.

How to expand treatment to more people plus switch those currently failing to an effective regimen, all within a framework of cutting back on donor spending?

As the absolute numbers of people who need access to second-line regimens continue to grow, addressing the high cost of second-line regimens will become increasingly important to ensure the most cost-effective use of available resources. A third-line treatment is currently US$ 2766 in low-income, US$ 5870 in middle-income countries.

Future Funding

As funding stalls, major funders – US, UK, Netherlands, France, Germany, Norway and Sweden – may be becoming fatigued. In 2001 at the UNGCP meeting, recipient countries were asked to dedicate 15% of their national budgets to health, agreed to n theory by the Abuja Declaration. Only 8 countries have done so. More than half of African countries spend less than the UN minimum of 34 US$ per capita.

New strategies have to be developed – small taxes on currency transactions, etc. Small airline ticket tax from many countries (see above). Product (Red) is a fund-raiser of the Global Fund that coordinates profits from sales from partner businesses and has recently reached the USD 170 million mark.

As mainstays of program centers are at best maintaining previous amounts (flat-funding, like PEPFAR) or unclear about their budgets for this year (GFATM), it is important that we all contribute, both economically and using advocacy, about how to continue to arrive to the amount needed (USD 25.1 billion/yr).

Europe gets involved

The European Union can impact access to medicines for developing countries through its policies, legislation and bilateral and regional trade agreements. The EU can adopt appropriate measures to improve access to existing medical tools (medicines, diagnostics, vaccines) as well as stimulate the research and development of better tools for people in resource-starved countries. The Working Group on Innovation, Access to Medicines and Poverty-Related Diseases will create a meaningful dialogue between Members of the European Parliament, the European Commission, and civil society.

More problems than solutions

It is quite possibly easier to flag the difficulties than offer or implement solutions, but one survey was recently carried out, this time by Oxfam. In a recent analysis of meeting the Millenium Development Goals, they criticized Europe overall as not valuing poor people “enough to … guarantee … by making aid commitments legally binding. … This year alone, the EU is 19 billion euros short of its targets … enough to have saved 3 million lives in poor countries.” They have started a Robin Hood tax (a tiny tax on bankers that could generate billions of US$). In their blog, they say that donors are not transparent with how their money is spent and where. For example, they highlight Kenya, where PEPFAR purportedly spent over one 500 million dollars on AIDS programs in 2008. A representative of the Kenyan Ministry of Health says that they cannot get “a list of partners, where they are working, how much they are spending, on what” from the US ( Which makes an integrated strategy on AIDS hard to accomplish. Without being too blithe, imagine that happening in the North: we knew how much we are spending, but not on what!

The unconscionable health gap: a global plan for justice

In the Lancet, Lawrence Gostin outlined a plan for health access for all (Gostin 2010). Despite robust international norms, health disparities render a person’s likelihood of survival drastically different depending on where she or he is born. WHO urges “closing the health gap in a generation” through action on the social determinants of health.

International health assistance has quadrupled over two decades rising to US$21.8 billion in 2007 (Ravishankar 2009). This level of funding might seem impressive but sits modestly beside the annual $1.5 trillion spent globally on military expenditures (2.43% of global gross domestic product), and $300 billion in agricultural subsidies.

Foreign aid simply is not predictable and scalable to needs and often reflects donors’ geostrategic interests rather than the key determinants of health. Developed countries recognize the health gap, but are resistant to taking bold remedial action.

If the health gap is unfair and unacceptable, how can the international community be galvanized to make a genuine difference? A global plan for justice would be a voluntary compact between states and their partners. It would simply encourage WHO to exercise its constitutional powers and leadership.

A global plan for justice would set achievable funding targets for a global health fund to be distributed according to need (Ooms 2008). Although WHO would negotiate the funding levels, developed countries could donate, for example, 0.25% of gross national income (GNI) per annum, in addition to current foreign assistance.

A global plan for justice would guarantee a universal package of essential services, comprising three core components: essential vaccines and medicines, basic survival needs, and adaption to climate change.

The international community must do more than lament ongoing, unconscionable health inequalities. It must act boldly and with a shared voice, such as through a global plan for justice. If the world does not act, the avoidable suffering and early death among the world’s least healthy people will continue unabated—a breach of social justice that is no longer ethically acceptable (Gostin 2010).

The amount of people who need access to ART in the next few years – in the short term – will grow substantially. Because of this, we need to keep up the pressure on all actors – donor organisations as well as individual nations, manufacturers, health care workers and affected communities of all sizes – to do their part in order to provide the most current and useful treatment strategies possible, to whole populations. In order to achieve this, we can not sit idly by and hope for the best – we must continue to push that boulder up the hill for as long as it takes so everyone who needs it has access to treatment and care as early and for as long as necessary.


Because global access is such a moving target, all references are web-based and in the text.


Collaborative Group on HIV Drug Resistance and UK CHIC Study Group. Long-term probability of detecting drug-resistant HIV in treatment-naïve patients initiating combination antiretroviral therapy. Clin Infect Dis 2010, 50: 1275-85.

Gostin L. The unconscionable health gap: a global plan for justice. Lancet 2010, 375:1504-5.

Harrigan RP. HIV drug resistance over the long haul. Clin Infect Dis 2010, 50: 1286-87.

Ooms G, Hammonds R. Correcting globalization in health: transnational entitlements versus the ethical imperative of reducing aid-dependency. Public Health Ethics 2008; 1: 154-170.

Ravishankar N, Gubbins P, Cooley RJ, et al. Financing of global health: tracking development assistance for health from 1990 to 2007. Lancet 2009; 373: 2113-2124.

Greener R. Financing the response to HIV in low- and middle-income countries: how it is affected by the economic crisis? UNAIDS presentation at IAS Rome, 20 July 2011., Untangling the web of antiretroviral price reductions, 14th edition, Medecins Sans Frontieres, July 2011.


Europe is Missing in Action,, 17 June 2010

FDA enforcement actions in the year 2008,


 “Punishing Success? Early Signs of a Retreat from Commitment to HIV/AIDS Care and Treatment”, November 2009, accessed online 29.04.10.

World Health Assembly. Reducing health inequities through action on the social determinants of health,, accessed Jan 4, 2010


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Filed under 6.13. Global Access to HIV Treatment, 6.9. Salvage Therapy, Part 2 - Antiretroviral Therapy