Despite advances in antiretroviral therapy that have revolutionized HIV disease management, effective control of the HIV infection pandemic remains elusive. Beyond the classic non-B endemic areas, HIV-1 non-B subtype infections are sharply increasing in previous subtype B homogeneous areas such as Europe and North America. As already known, several studies have shown that, among non-B subtypes, subtypes C and D were found to be more aggressive in terms of disease progression. Luckily, the response to antiretrovirals against HIV-1 seems to be similar among different subtypes, but these results are mainly based on small or poorly designed studies. On the other hand, differences in rates of acquisition of resistance among non-B subtypes are already being observed. This different propensity, beyond the type of treatment regimens used, as well as access to viral load testing in non-B endemic areas seems to be due to HIV-1 clade specific peculiarities. Indeed, some non-B subtypes are proved to be more prone to develop resistance compared to B subtype. This phenomenon can be related to the presence of subtype-specific polymorphisms, different codon usage, and/or subtype-specific RNA templates. This review aims to provide a complete picture of HIV-1 genetic diversity and its implications for HIV-1 disease spread, effectiveness of therapies, and drug resistance development.

/pdf/hiv-1-genetic-variability-and-clinical-implications-rsb6g2njvy.pdf

HIV-1 Genetic Variability and Clinical Implications.

https://www.thelancet.com/pdfs/journals/lanhiv/PIIS2352-3018(15)00087-9.pdf

Monitoring and switching of first-line antiretroviral therapy in adult treatment cohorts in sub-Saharan Africa: collaborative analysis

Highly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings.

Antiviral Drug Resistance and the Need for Development of New HIV-1 Reverse Transcriptase Inhibitors

Clinical management of HIV-1 resistance.

Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy.

https://www.mdpi.com/1999-4915/3/4/347/pdf

Clinical Management of HIV Drug Resistance

Susceptibility to etravirine (ETR), an expanded-spectrum nonnucleoside reverse transcriptase inhibitor (NNRTI), is dependent on the type and number of NNRTI resistance-associated mutations (RAMs). Studies have shown that some HIV-1 subtypes may have natural polymorphisms described as ETR RAMs. This study addresses the prevalence of ETR RAMs in treatment-naive patients infected with HIV-1 non-B subtypes and its potential impact on ETR susceptibility. The prevalence of ETR RAMs in 726 antiretroviral-naive patients infected with non-B HIV-1 subtypes was studied. ETR genotypic resistance was interpreted according to Agence Nationale de Recherches sur le SIDA and Stanford algorithms. NNRTI phenotypic susceptibilities of samples with at least one ETR RAM were measured. Overall, 75 (10.3%) of 726 sequences harbored at least one ETR RAM: sequences from 72 patients (10%) each had one ETR RAM, and sequences from 3 patients (0.4%) each had two ETR RAMs (V90I and Y181C in one case and V90I and A98G in two cases). None of the viruses had three or more ETR RAMs, and none were consequently classified as resistant to ETR. All sequences with two ETR RAMs belonged to subtype CRF02_AG. The presence of one ETR RAM was statistically more frequent in subtype CRF02_AG than in other non-B subtypes (P = 0.004). Three new mutation profiles (E138A and V179I, Y181C and H221Y, and V90I and Y181C) showing decreased ETR phenotypic susceptibility were identified. In conclusion, although the prevalence of ETR RAMs in treatment-naive patients infected with non-B HIV-1 subtypes was 10%, in most cases this had no significant impact on ETR susceptibility. However, the transmission of drug-resistant viruses with Y181C in a non-B genetic background has a potential for impact on ETR susceptibility.

/pdf/resistance-associated-mutations-to-etravirine-tmc-125-in-b91k0dp81t.pdf

Resistance-Associated Mutations to Etravirine (TMC-125) in Antiretroviral-Naïve Patients Infected with Non-B HIV-1 Subtypes

In sub-Saharan Africa, while antiretroviral therapy (ART) becomes widely available, access to biological measurements to monitor patients under ART remains scarce, making the management of ART difficult. We described the management of switching to second-line ART where HIV care is provided mainly in secondary health-care structures, in the region of Segou, Mali. Of 865 patients, followed under ART for a median time of 15 months, 40 switched to second-line ART (3.3 switches/100 person years). Reason for switching was failure in 18 patients (after 21 months in median) and severe intolerance in 13 (after three months in median). Switching to second-line ART occurred earlier when motivated by intolerance than by failure. The low rate of switch compares well with other studies, but was low compared to the expected rate of failure, and may indicate that physicians are reluctant to switch ART when treatment options are limited.

Switch to second-line ART in West African routine care: incidence and reasons for switching

OBJECTIVES: To describe HIV-1 variants circulating in Mali and to estimate the rate of transmission of HIV-1 drug resistance in 2006. PATIENTS AND METHODS: Viral reverse transcriptase (RT) and protease (PR) genes from 198 antiretroviral (ARV)-naive patients diagnosed HIV-1 positive in May 2006 in Bamako and Segou were sequenced. RESULTS: Although CRF02_AG was always the predominant HIV-1 subtype observed (72%) a higher genetic diversity than that in 2005 was observed. The overall prevalence of primary resistance is 11.5% in Mali in 2006 according to the 2007 IAS-USA list of mutations [nucleoside RT inhibitor (NRTI): 1.5% non-NRTI (NNRTI): 9% and PI: 1%] and 2.5% (NRTI: 1% NNRTI: 1.5% and PI: 0%) according to the Stanford list of mutations. There was no significant difference between 2005 and 2006 in the overall primary resistance prevalence or in the prevalence of mutations in the different ARV classes. Resistance mutations found in RT and PR genes are in agreement with the highly active antiretroviral therapy regimen available in Mali except for V90I V106I and A98G mutations which are associated with etravirine resistance but polymorphic in non-B subtypes. CONCLUSIONS: HIV-1 genetic diversity seems increased in Mali but the overall HIV-1 primary resistance prevalence remains low. This is consistent with the findings from other West African countries where prevalence rates are lower than 5%. However considering the large scaling up of ARV use in this country it is necessary to regularly monitor the development of primary resistance in Mali.

/pdf/evolution-of-genetic-diversity-and-drug-resistance-mutations-n0d7q4cweh.pdf

Evolution of genetic diversity and drug resistance mutations in HIV-1 among untreated patients from Mali between 2005 and 2006

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Resistance-Associated Mutations to Etravirine (TMC-125) in Antiretroviral-Naïve Patients Infected with Non-B HIV-1 Subtypes

Switch to second-line ART in West African routine care: incidence and reasons for switching

Evolution of genetic diversity and drug resistance mutations in HIV-1 among untreated patients from Mali between 2005 and 2006