Vidya Madhavan

High Frequency of Clinically Significant Mutations after First-Line Generic Highly Active Antiretroviral Therapy Failure: Implications for Second-Line Options in Resource-Limited Settings

Continuation of failed highly active antiretroviral therapy regimens can lead to the accumulation of mutations that may limit options for second-line treatment. We studied the pattern of drug resistance mutations among 138 Indian patients who experienced failure of nonnucleotide reverse-transcriptase-containing first-line highly active antiretroviral therapy. This study demonstrates a high frequency of drug resistance mutations in human immunodeficiency virus-infected Indians who experience immunologic treatment failure and suggests the need for viral load monitoring.

Primary HIV-1 Drug Resistance and Polymorphic Patterns Among Injecting Drug Users (IDUs) in Chennai, Southern India

Background and Objective: India has 1.1 million injecting drug users (IDUs) with an HIV prevalence rate as high as 64%. Drug resistance screening before therapy is beneficial to the individual. Here, we have studied primary drug resistance among IDUs in Chennai. Methods: Specimens (n = 55) collected between March 2005 and April 2006 were subjected to genotyping assay. The mutations for the drug resistance were interpreted using the Stanford HIV Drug Resistance Database. Results: M41LM (1.8%), K65KN (1.8%), and G73GS (2.7%) were found to be associated with low-level resistance to zidovudine (ZDV), stavudine (d4T), abacavir (ABC), didanosine (ddI), emtricitabine (FTC), tenofovir (TDF), and saquinavir (SQV) in each specimen. The rate of polymorphisms is significantly different from universally established subtype ‘‘C’’-specific polymorphisms (P < .0001). Conclusion: The presence of drug resistance mutations, though minimal, is alarming as it could spread easily between IDUs and from them to their sexual partners. The genetic variation is of importance in vaccine design.

Correlates of HIV and malaria co-infection in Southern India

BackgroundMalaria and HIV co-infection adversely impact the outcome of both diseases and previous studies have mostly focused on falciparum malaria. Plasmodium vivax contributes to almost half of the malaria cases in India, but the disease burden of HIV and P. vivax co-infection is unclear.MethodsHIV-infected subjects (n=460) were randomly selected from the 4,611 individuals seen at a Voluntary Counseling and Testing Center in Chennai, India between Jan 2 to Dec 31 2008. Malaria testing was performed on stored plasma samples by nested PCR using both genus-specific and species-specific primers and immunochromatography-based rapid diagnostic test for detecting antibodies against Plasmodium falciparum and P. vivax.ResultsRecent malaria co-infection, defined by the presence of antibodies, was detected in 9.8% (45/460) participants. Plasmodium vivax accounted for majority of the infections (60%) followed by P. falciparum (27%) and mixed infections (13%). Individuals with HIV and malaria co-infection were more likely to be men (p=0.01). Between those with and without malaria, there was no difference in age (p=0.14), CD4+ T-cell counts (p=0.19) or proportion CD4+ T-cell below 200/mL (p=0.51).ConclusionsRetrospective testing of stored plasma samples for malaria antibodies can facilitate identification of populations with high rates of co-infection, and in this southern India HIV-infected cohort there was a considerable burden of malaria co-infection, predominantly due to P. vivax. However, the rate of P. falciparum infection was more than 6-fold higher among HIV-infected individuals than what would be expected in the general population in the region. Interestingly, individuals co-infected with malaria and HIV were not more likely to be immunosuppressed than individuals with HIV infection alone.

High Prevalence of Hepatitis Delta Virus among Patients with Chronic Hepatitis B Virus Infection and HIV-1 in an Intermediate Hepatitis B Virus Endemic Region

We conducted a study to investigate HIV and hepatitis delta virus (HDV) coinfection among patients with chronic hepatitis B virus (HBV) infection and the triple infection’s (HIV/HBV/HDV) clinical implications in India, an intermediate HBV endemic region, with an estimated HIV-positive population of 2.5 million. A total of 450 patients (men: 270; women: 180) with chronic HBV infections and 135 healthy volunteers were screened for HIV and HDV. The incidence of the triple infection was low (4 [0.8%]) compared with dual infections of HIV-1/HBV (7 [1.5%]) and HBV/HDV (22[4.8%]). Among 21- to 40-year-olds, HBV/HDV coinfection (45.8%) and HBV/HDV/HIV-1 triple infection was predominant (75%). Among 11 patients coinfected with HIV-1/HBV, 4 (36%) were tri-infected and were also associated with chronic hepatitis and cirrhosis. The HDV coinfection was higher among patients coinfected with HBV/HIV-1, despite the declining trend in HDV infection among HIV-negative patients, as previously reported. Thus, it is important to assess the impact of HIV, chronic HBV, and HDV tri-infection in India.

Short Communication: Analysis of Selection Pressure and Mutational Pattern of HIV Type 1 Reverse Transcriptase Region Among Treated and Nontreated Patients

Variation of the HIV-1 subtype C reverse transcriptase region (RT) resulting in response to the selective pressures of drug therapy remains poorly characterized. Here, we compared the genetic variation resulting in the presence and absence of antiretroviral drug selective pressures on HIV-1 subtype C RT among nontreated and treated patients. The nucleotide variability, nonsynonymous and synonymous ratio, and the positively selected mutations were determined by comparing the RT sequences isolated at two time points among nontreated (baseline and follow-up) and treated patients (baseline and treatment failure). Compared to the nontreated patients, the intrapatient nucleotide variability, the number of nonsynonymous and synonymous substitutions was significantly higher among the treated patients. Among the mutations positively selected, the frequency of D121Y, I135R, and Q207E increased and the frequency of mutation S48T decreased significantly during treatment failure. Further studies are essential to discover the role of these mutations during treatment in HIV-1 subtype C.

Reverse transcriptase substitution at codons 208 and 228 among treatment-experienced HIV-1 subtype-C-infected Indian patients is strongly associated with thymidine analogue mutations.

In HIV-1 subtype C infected populations in south India, we searched for novel mutations associated with failing antiretroviral therapy that included nucleoside reverse transcriptase (RT) inhibitors. HIV-1 RT sequences were generated from treated and untreated groups and each nucleotide position was analysed with appropriate corrections for multiple testing. We found that nonsynonymous mutations at positions 208 and 228 were strongly associated with the presence of thymidine analogue mutations in the treated group, and were not present at all in the naive group. The role of these substitutions on treatment outcomes and the evolution of drug resistance in HIV-1 subtype-C infected populations warrant further investigation.

The association between HIV-1 subtype C antiretroviral resistance and HLA prevalence in southern India.

This letter to the editor discusses a study of 45 patients protease (PR) and reverse transcriptase (RT) sequences who were receiving second-line antiretroviral treatment (ART) therapy to investigate how a number of common antiretroviral drug resistance mutations in HIV pol affect cytolytic T lymphocytes (CTL) recognition with relation to a predefined specific HLA allele derived peptide.

HIV-1 reverse transcriptase nucleotide substitutions in subtype C-infected, drug-naive, and treatment-experienced patients in South India.

In this large cohort of patients infected with HIV-1 subtype C, virologic failure during antiretroviral therapy was associated with high rates of resistance; however, many nucleotide changes were not congruent with previously documented resistance associated mutations. These data may have implications in interpreting genotypic resistance of HIV-1 subtype C during therapy failure.