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Maglione M, Goetz MB, Wang Z, et al. Antiretroviral (ARV) Drug Resistance in the Developing World. Rockville (MD): Agency for Healthcare Research and Quality (US); 2007 Sep. (Evidence Reports/Technology Assessments, No. 156.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Antiretroviral (ARV) Drug Resistance in the Developing World

Antiretroviral (ARV) Drug Resistance in the Developing World.

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The primary limitations of this review are the quality and quantity of the available studies. Other limitations related specifically to how the studies were conducted, including heterogeneity with respect to study design, the lack of inclusion of participants infected with more unusual viral clades, and failure to stratify data on treatment-naïve patients by demographic or risk variables.

The quantity of studies we were able to include was limited by the fact that we considered only studies whose results were published or were presented at major scientific conferences. Our search strategies were comprehensive, but it is possible we did not identify all published work. One function of the peer review process is to identify published studies we missed. In addition to the information obtained from published studies, it is possible that substantially more information regarding prevalence and predictors of resistance might have been available via new analyses of existing large datasets such as WATCH or the Stanford University HIV RT and Protease Sequence Database.

The quality of the studies we identified was affected by two types of problems. The first is basic to all epidemiologic studies. Of high importance in studies that are primarily concerned with estimation - as are these studies of the frequency of resistance- is the representativeness of the studied population relative to some larger population of interest. In this case, the larger population of interest is usually something like “all treatment-naïve patients in the country [or some defined geographic area]” or “all patients infected with HIV clade C who have failed to respond to an initial treatment by time T with drugs X, Y, and Z.” Most identified studies either did not state how participants were selected for resistance-testing or spelled out methods that did not allow the reader to understand how representative the studied population was relative to a larger population of interest. Without such information, generalizing the results of identified studies to the inhabitants of a specific region is hazardous. The second problem is the small sample sizes of most of the identified studies, relative to the numbers of patients estimated to have HIV in the countries of interest. Given plausible assumptions regarding variability within populations, data derived from samples of 100 or 200 HIV-infected patients in a country with perhaps millions of infected persons cannot be extrapolated to that whole population with any confidence.

The studies were heterogeneous regarding the timing and frequency of ARV resistance tests, the sensitivity of the assay for ARV resistance, and whether clade-specific analyses of ARV resistance were performed. This makes direction comparisons between groups difficult. The pMTCT studies were also quite heterogeneous in terms of the duration and type of ARV treatment.

Data on HIV clades other than A, B, C, D, or the recombinant types were scarce. Only two studies which stratified results by clade reported data on clades F, G, K, J, and others. The samples were very small for those clades; the largest was 11 persons for clade F. Thus, results should be interpreted with caution.

Finally, many studies of treatment naïve persons did not stratify the resistance data by variables of interest such as gender and mode of transmission, although that data was often available. That being said, many sample sizes were small enough that stratification would have lacked statistical power to detect real differences.

Conclusions and Recommendations for Future Research

In Latin America, nine studies identified rates of resistance to NRTIs ranging from 2 to 14 percent among treatment-naïve groups. Reported rates of resistance to NNRTIs were low, ranging from zero to two percent. In a handful of studies that included Brazilian and Argentinian populations, PI polymorphisms were common, presumably among persons with HIV clade B. We found no studies of HIV resistance in Central America.

In Africa, studies identified NNRTI resistance rates from 0 percent to 7.7 percent associated with infection with most HIV clades. NRTI resistance rates ranged from 0 percent to 8 percent for all clades. Primary PI mutations were rare (<3 percent) among Africans; polymorphisms were widespread.

We found published data from only three studies in India; these studies varied in their results. As India has a relatively high prevalence of HIV infection, more research on resistance patterns should be a priority. We found only three studies from other developing regions of Asia. None reported NNRTI resistance. NRTI resistance ranged from 4 to 7 percent; primary resistance to PIs ranged from 2 to 3 percent.

Few published studies stratified resistance data by host characteristics such as mode of HIV transmission, risk factors, or gender, although these data were collected in most of the studies. Studies with larger sample sizes would allow meaningful analyses of patterns among groups, for example MSM, heterosexuals, prostitutes, and IDUs. In addition, data on HIV clades other than A, B, C, D, or the recombinant types were too scarce to permit reliable conclusions. In future studies, rare HIV clades should be over-sampled in order to provide statistically meaningful data.

Evidence provided by longitudinal analyses suggests that the prevalence of NNRTI resistance may vary with time since treatment among women taking SD-NVP to prevent mother-to-child transmission of HIV. In one study, fading of variants with Y181C was reported in women infected with clade A but not clade D. Y181C may have less effect on viral fitness of clade D than on A; this observation warrants further investigation in future studies. The impact of the Y181C mutation should also be studied in clades other than D and A.

A randomized comparison of outcomes in women receiving pMTCT with SD-NVP alone, versus SD-NVP followed by a “tail” of 3 or 7 days of ZDV and 3TC found that the prevalence of NNRTI resistance in these three groups was 57 percent, 13 percent, and 9 percent, respectively. In a substudy of this trial, highly sensitive allele-specific RT-PCR assays detected the K103N mutation or Y181C resistance mutations in 75 percent of women receiving SD-NVP versus 27 percent of women receiving SD-NVP plus 3 or 7 days of ZDV and 3TC. The ideal “tail” regimen and duration needs to be researched; drugs other than ZDV and 3TC could be studied in both mothers and infants. The use of a “tail” to prevent resistance needs to be evaluated with SD-NVP alone but also with SD-NVP plus a short course of ZDV, because resistance can occur even when ZDV is given. At least two trials evaluating the use of “tails” are currently in progress.

In one study, women who received either intrapartum SD-NVP or placebo following daily ZDV during their third trimester were put on three-drug ARV postpartum. Intrapartum SD- NVP was statistically associated with virologic failure at both 3 and 6 months, as were NRTI and NNRTI mutations. In another study, in which women were put on three-drug ARV after intrapartum SD-NVP or placebo, virologic failure was strongly associated with intrapartum SD-NVP among women who started ARV within 6 months postpartum, but not among women who started ARV 6 months or more postpartum. Importantly, several trials suggest that when the infant receives SD-NVP at birth in the background of ZDV, maternal SD-NVP does not provide any additional protection. This finding should be researched further, as should the ideal time to start ongoing postpartum ARV treatment.

We identified few studies designed to assess the effect of health services delivery factors or medication adherence on the development of resistance in patients in developing countries. Where resources permit, studies of adherence in developing regions should conduct resistance testing and report results. In addition, observational studies of HIV treatment in developing regions should ask questions about factors affecting patient access to medication.

Studies using phenotype assessments were rare in developing regions. Funding of such studies is recommended due to their increased specificity. More studies should use ultrasensitive assays to determine not just frequency of resistance as “all or none” but also the quantitative frequency of resistance mutations and types of mutations over time, which may be important in terms of response to therapy. Patients, including mothers and their HIV positive children, should be followed over several years where possible, to assess the extent and quantity of archiving of resistance mutations in cells.

Published data on resistance in developing regions, particularly India, Southeast Asia, and Central America, are scarce. Resistance surveillance programs should be established throughout the developing world. Data should be reported and analyzed in a consistent and timely fashion. To this end, the World Health Organization (WHO) recently launched the Global HIV Drug Resistance Surveillance Network (HIV Resent).

The Stanford University database and the WATCH program based in the Netherlands collect resistance data from all over the world. It is critical that their data be continually updated and analyzed so that trends in resistant mutations can be recognized quickly and addressed. The WATCH program recently reported that only 58 percent of the researchers asked to share individual-level protease and RT sequences agreed. It is crucial that this level of collaboration be improved.


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