Highly active antiretroviral therapy (HAART) has led to dramatic decline in morbidity and mortality among HIV-infected persons both in developed and developing countries [1–3]. The release of the WHO treatment guidelines for antiretroviral therapy (ART) enabled an evidence-based, simplified, and systematic approach to the prescription of HAART appropriate for resource-limited settings. Now that the availability of HAART has exploded across resource-limited settings, new challenges have arisen with regard to growing treatment resistance.
Despite the evolution of WHO recommendations to reflect the latest research on development of HAART resistance, the challenge of resistance is a real and looming threat to the long-term success of HAART, particularly in resource-limited settings. Surrogate measurements for failure of ART in places where plasma viral load monitoring is not readily available are increasingly shown to be inadequate to prevent resistance . Furthermore, lack of available genotypic testing in most resource-limited settings necessitates definitive guidelines for empiric second-line and third-line treatment options supported by robust data.
The article summarizes standardized recommendations for first-line and second-line HAART, as well as recent research on resistance development to HAART, in an attempt to better understand the effect of accumulated resistance mutations on current standardized treatments. It focuses on resource-limited settings as these are where issues of resistance pose the biggest challenges. It also summarizes the latest research impacting the development and evolution of newer recommendations for first-line, second-line, and even third-line HAART in resource-limited settings where lack of plasma viral load monitoring and resistance-mutation genotyping may pose significant barriers to successful long-term HAART.
FIRST AND SECOND-LINE HAART
Until 2010, the first-line HAART consisted of zidovudine (AZT) or stavudine (d4T) in combination with lamivudine (3TC) and nevirapine (NVP) or efavirenz (EFV) in resource-limited settings [5,6]. In resource-rich settings, tenofovir (TDF) therapy is preferred as the nucleoside reverse transcriptase inhibitor (NRTI) backbone in first-line HAART regimens. This is because TDF has minimal adverse-event profile compared to other NRTIs in its class. Additionally, such TDF-containing regimens are now available in a combination as a fixed-dose single-tablet regimen (STR) . This TDF-containing combination drug is marginally more expensive than AZT-containing regimens. Studies on cost efficacy of HAART very clearly show that TDF-containing first-line therapy is more cost-effective over a long period when compared with AZT or d4T-containing therapies as a result of the latter drugs’ increased toxicity profiles . Finally, the PEARLS study revealed that first-line therapies containing TDF are superior to therapy with AZT due to adverse side effects of AZT . As a result of these numerous findings, the WHO treatment guidelines and other national guidelines in resource-limited countries have also begun to recommend TDF to be included in first-line HAART regimens at the initiation of therapy . Several generic manufacturers now make STRs containing TDF, EFV, and either 3TC or FTC, making them widely available in resource-limited settings. The current WHO treatment guidelines clearly recommend this fixed-dose combination with TDF as the preferred regimen for treatment initiation .
In resource-limited settings, d4T was formerly amongst the most commonly used medications in HAART because of its low cost, efficacy, and wide availability. However, due to the potent mitochondrial toxicity associated with long-term use of d4T, many countries are phasing it out of combination therapies. In its revised 2010 and 2013 guidelines, the WHO recommended transitioning away from the use of d4T even in patients without documented virologic failure .
Given this rapidly changing landscape of first-line HAART in resource-limited settings, it is important to understand the extent of NRTI cross-resistance amongst those with virologic failure on d4T-containing first-line therapy or amongst those without documented virologic failure who are to be switched to TDF, as per the WHO recommendations. Knowledge of these mutations and their implications for subsequent therapy can impact the use of the TDF and AZT in significant ways. A recent review article published in 2013 in the Journal of Infectious Diseases looked at precisely this issue. In an analysis of the two major mutational pathways developed to d4T-based therapy, each with varying implications for subsequent TDF- and AZT-based therapy, the study took multiple variables into account, including duration of first-line therapy and concomitantly prescribed non-nucleoside reverse transcriptase inhibitors (NNRTIs). They concluded that regardless of the reason for transitioning from d4T (for either virologic failure or avoidance of long-term toxicity), TDF is more advantageous than AZT for the majority of patients in resource-limited settings where genotypic resistance testing is unavailable. In settings where genotypic testing is available, the small subset of patients can be identified for whom AZT is more advantageous choice than TDF in combination therapy [11▪].
As such, in resource-limited settings, patients who fail first-line therapy containing AZT are switched to a TDF-based regimen and vice versa. NNRTIs such as NVP or EFV are also switched to protease inhibitors boosted with ritonavir. Among the boosted protease inhibitor (bPI) regimens, atazanavir (ATVr) or lopinavir (LPVr) are the primary choices for second-line therapy as per the recommended public health approach . The tolerability and effectiveness of these second-line regimens are shown to be good from published reports from resource-limited settings [12,13].
In a meta-analysis published in 2013, the possibility of a bPI-based first-line HAART regimen was examined in comparison with the standard NRTI/NNRTI first-line regimens. This was done in an effort to establish whether bPIs as first-line medications could decrease the number of resistance mutations to NRTIs that are seen increasingly in resource-limited settings where TDF is now used more frequently. The meta-analysis incorporated relevant randomized studies directly comparing first-line recommended NNRTIs (NVP and EFV) in resource-limited settings, with bPIs that are either currently used in these settings or are promising candidates in these settings [ATV and darunavir (DRV)]. The NRTI backbones included in the study were TDF and abacavir (ABC). Amongst the trials included in the analysis, the study found that there was no difference in the rate of virologic failure in the NNRTI versus bPI arms. However, there were significant differences in occurrence of particular genotypic mutations conferring resistance to NRTIs after virologic failure, including the M184V/I and the K65R mutations, with the mutations occurring less often in the bPI arm of the analysis. There was no evidence of significant genotypic heterogeneity conferring treatment resistance between either of the bPIs in the trial. Despite these notable findings, the authors concluded that although the information gleaned could inform future decisions to switch first-line HAART to well tolerated bPI-based regimens in resource-limited settings, the findings need to be weighed against other factors. These considerations include cost, availability of fixed-dose combinations, toxicity, co-administration of tuberculosis treatment, and finally, and perhaps most importantly, the lack of available second-line regimens following protease inhibitor-based first-line therapy. This lack is due to the increased risk of mutations with NRTI/NNRTI-based second-line regimens [14▪]. Other studies have also looked at cost-efficacy of a first-line bPI-based regimen in resource-limited setting and have found mixed results of the utility of such action [15▪]. Thus, these findings will continue to be important for future decisions when other classes of drugs may become available for second-line treatment options. LPV monotherapy with intensification with TDF/FTC if not virologically suppressive at week 16 was shown to be efficacious in a pilot study conducted over a 104 weeks’ duration by AIDS Clinical Trials group . This concept should be studied in randomized trials with other once-daily boosted protease inhibitors like DRV.
Darunavir is currently preserved as a third-line or salvage medication in resource-limited settings. This recommendation is supported by published data based on the pattern of resistance mutations to currently used second-line protease inhibitors like ATV and LPV . Preserving DRV for salvage can jeopardize its efficacy if viral load monitoring is not done on the currently used boosted protease inhibitor second-line options in resource-limited settings due to the accumulated mutations to protease inhibitors . Clinical trials have shown the superior efficacy and better safety profile of DRV as part of a second-line regimen. The ARTEMIS study even showed that once-daily ritonavir-boosted DRV/r is noninferior to LPV/r as a first-line regimen in treatment-naive patients at 48 weeks, and has a better safety profile . Recent guidelines have recommended once-daily DRV/r as a second-line medication for those patients who have failed first-line HAART consisting of NNRTIs with an NRTI backbone. DRV/r monotherapy as maintenance therapy after virological suppression has been shown well in the Monet trial . Single-pill DRV/r and the newer integrase inhibitor doultegravir (DTG) would be a perfect choice for the resource-limited settings as a strong and durable second-line therapy option.
VIRAL LOAD MONITORING
Viral load monitoring is not the standard of care in resource-limited settings because of the cost or mere lack of adequate technology. During antiretroviral treatment failure, virologic failure, as defined by the WHO treatment guidelines as a persistent viral load greater than 1000 copies after a treatment period of at least 6 months, occurs first. This is followed by immunological failure, defined as a drop in CD4 cell counts to or below baseline levels after 6 months of therapy, persistent CD4 levels below 100 cells/μl after 6 months of therapy, or at least a 50% decrease in CD4 cell counts from the peak of CD4 cell counts during treatment. The clinical criterion for failure is the development of one or more AIDS-defining illnesses after 3 or more months of HAART . Modeling studies have shown that the duration of time between virologic failure and immunological failure can be anytime between 6 months to 2 years . Resistance mutations occur along with or even prior to virologic failure and can accumulate while a patient is continued on the failed regimen. This typically occurs in settings where viral load monitoring or second-line therapy options are unavailable . In particular, a study from southern India found that if viral load monitoring is not available, severe resistance mutations occur to current first-line HAART regimens. These mutations might jeopardize the use of other NRTIs, such as TDF, ABC, or didanosine (ddI), in second-line regimens. Such mutations can also place at risk the successful use of newer NNRTI drugs that are currently under development . Similar observations were also reported in Thailand, Uganda, Zimbabwe, and in Malawi [23–25].
According to a recent review on the rates of virologic failure in developing countries, multiclass drug resistance is proven to occur with increasing time on HAART [26▪]. Since the rollout of HAART in Sub-Saharan Africa in particular, the prevalence of mutations to HAART has increased over time, particularly those to the NNRTI class of drugs as reported by studies in east and southern Africa [15▪,27▪]. Thus, if AZT or d4T containing first-line HAART regimens are used along with immunological monitoring, NRTIs used in second-line therapy combinations among other possible classes of medications might be ineffective due to the accumulation of severe mutations to these medication regimens. Furthermore, recent studies have shown that NNRTI-containing first-line therapies may also limit second-line options in countries where resources are limited [28▪]. Finally, the mere availability of second-line and third-line regimens in resource-limited settings is an issue because of high cost. Multitudinous patients who have failed first-line therapy are still not receiving subsequent optimal therapy as a result of this [29▪▪].
To study the need for newer classes of medications such as integrase inhibitors along with protease inhibitors for the creation of effective second-line therapy in such situations, a large, randomized, multisite trial was carried out on 650 patients. This trial showed the combination of the integrase inhibitor, raltegravir, in combination with LPV is noninferior to the HAART regimen containing NRTIs and boosted protease inhibitors, as recommended by the WHO . Two other multisite trials (ACTG 5273-SELECT, ARROW) are currently underway in an effort to substantiate these findings.
Given the increasing rate of patients switching to second-line therapy after failing first-line regimens, a recent review article looked at the rates of virologic failure on second-line therapy in resource-limited settings. They found that there was a high incidence of second-line failure. It was thought that this was mostly due to poor adherence rather than drug resistance, as evidenced by the few relevant studies assessing both parameters. However, given limited access to treatment options beyond second-line regimens in addition to few international and national guidelines on this issue, the authors correctly highlighted the need for routine virologic monitoring as well as future research on additional therapies for patients experiencing virologic failure on second-line regimens .
Increasing numbers of patients are benefiting greatly from the rapid scale-up of ART in resource-limited settings. But with limited laboratory monitoring due to barriers of high cost, there may be unidentified treatment failures which can jeopardize commonly used and recommended first-line and second-line HAART regimens [4,15▪,29▪▪]. Surveillance for HAART resistance in HIV has been important to treatment recommendations made by the WHO. It typically includes monitoring for early signs of poor treatment performance, surveillance of transmission of drug resistance (TDR), and evaluation of mutations responsible for drug resistance while on therapy . Currently, the majority of resistance surveillance in resource-limited settings is conducted when viral load is detected to be above 1000 copies/ml. Additional resistance can be identified if lower viral load thresholds are used. However, resistance becomes more complex and difficult to manage when viral load monitoring is unavailable to identify treatment failure, allowing the added accumulation of resistance mutations when a failing regimen is continued, as previously described [32▪▪].
The generally recognized concern is that potentially long periods of unrecognized viral failure will permit the transmission of drug-resistant strains, compromising the standard treatment regimens currently recommended internationally. According to an analysis from 2013 looking closely at the issue of TDR, there is limited evidence regarding the rate of transmission of resistant HIV strains in the developing world [15▪]. Thus, the question remains as to what the critical threshold for TDR is, above which taking cost-effective public health action is warranted. Whereas access to resistance testing is not readily available in most resource-limited settings, recently developed mathematical models suggest that the effect of moderate to high levels of TDR on mortality could be significant over the long term, making it extremely important to carefully monitor the transmission of resistant HIV strains [15▪]. Newer-class drugs are traditionally much more expensive than what is currently available. Hence, investing in viral load monitoring and identifying early treatment failure in order to switch patients to standard second-line therapies could be the most cost-effective solution.
There is an urgent need to implement cost-effective, simple, low-tech viral load monitoring in resource-limited settings to sequence ART. With the availability of fixed-dose STR for first-line ART, efforts should be made to implement once daily second-line ART options. With the scale-up of second-line therapy in resource-limited settings, there is a need to make available newer antiretroviral drugs for third-line/salvage option to provide sustained good quality of life to persons with HIV disease.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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