Delayed identification of treatment failure causes high levels of acquired drug resistance and less future drug options among HIV-1-infected South Indians.

PURPOSE: HIV-1 Drug Resistance Mutations (DRMs) among Immunological failure (IF) on NRTI based first-line regimens, Thymidine analogue (TA) - AZT & D4T and Non-Thymidine Analogue (NTA) -TDF; and predict viral drug susceptibility to gain vision about optimal treatment strategies for second-line. METHODS: Cross-sectionally, 300 HIV-1 infected patients, failing first-line HAART were included. HIV-1 pol gene spanning 20-240 codons of RT was genotyped and mutation pattern was examined, (IAS-USA 2014 and Stanford HIV drug resistance database v7.0). RESULTS: The median age of the participants was 35 years (IQR 29-40), CD4 T cell count of TDF failures was low at 172 cells/µL (IQR 80-252), and treatment duration was low among TDF failures (24 months vs. 61 months) (p < 0.0001). Majority of the TDF failures were on EFV based first-line (89 % vs 45 %) (p < 0.0001). Level of resistance for TDF and AZT shows, that resistance to TDF was about one-third (37 %) of TDF participants and onefourth (23 %) of AZT participants; resistance to AZT was 17 % among TDF participants and 47 % among AZT participants; resistance to both AZT and TDF was significantly high among AZT participants [21 % vs. 8 %, OR 3.057 (95 % CI 1.4-6.8), p < 0.0001]. CONCLUSION: Although delayed identification of treatment failure caused high levels of acquired drug resistance in our study. Thus, we must include measures to regularize virological monitoring with integrated resistance testing in LMIC (Low and Middle Income Countries) like in India; this will help to preserve the effectiveness of ARV and ensure the success of ending AIDS as public health by 2030.

High discordance in blood and genital tract HIV-1 drug resistance in Indian women failing first-line therapy.

Objectives: Examine HIV-1 plasma viral load (PVL) and genital tract (GT) viral load (GVL) and drug resistance in India. Methods: At the YRG Centre for AIDS Research and Education, Chennai, we tested: PVL in women on first-line ART for ≥6 months; GVL when PVL >2000 copies/mL; and plasma, genital and proviral reverse transcriptase drug resistance when GVL >2000 copies/mL. Wilcoxon rank-sum and Fisher's exact tests were used to identify failure and resistance associations. Pearson correlations were calculated to evaluate PVL-GVL associations. Inter-compartmental resistance discordance was evaluated using generalized estimating equations. Results: Of 200 women, 37% had detectable (>400 copies/mL) PVL and 31% had PVL >1000 copies/mL. Of women with detectable PVL, 74% had PVL >2000 copies/mL, of which 74% had detectable GVL. Higher PVL was associated with higher GVL. Paired plasma and genital sequences were available for 21 women; mean age of 34 years, median ART duration of 33 months, median CD4 count of 217 cells/mm3, median PVL of 5.4 log10 copies/mL and median GVL of 4.6 log10 copies/mL. Drug resistance was detected in 81%-91% of samples and 67%-76% of samples had dual-class resistance. Complete three-compartment concordance was seen in only 10% of women. GT-proviral discordance was significantly larger than plasma-proviral discordance. GT or proviral mutations discordant from plasma led to clinically relevant resistance in 24% and 30%, respectively. Conclusions: We identified high resistance and high inter-compartmental resistance discordance in Indian women, which might lead to unrecognized resistance transmission and re-emergence compromising treatment outcomes, particularly relevant to countries like India, where sexual HIV transmission is predominant.

Etravirine and Rilpivirine Drug Resistance Among HIV-1 Subtype C Infected Children Failing Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens in South India.

We have analyzed reverse transcriptase (RT) region of HIV-1 pol gene from 97 HIV-infected children who were identified as failing first-line therapy that included first-generation non-nucleoside RT inhibitors (Nevirapine and Efavirenz) for at least 6 months. We found that 54% and 65% of the children had genotypically predicted resistance to second-generation non-nucleoside RT inhibitors drugs Etravirine (ETR) and Rilpivirine, respectively. These cross-resistance mutations may compromise future NNRTI-based regimens, especially in resource-limited settings. To complement these investigations, we also analyzed the sequences in Stanford database, Monogram weighted score, and DUET weighted score algorithms for ETR susceptibility and found almost perfect agreement between the three algorithms in predicting ETR susceptibility from genotypic data.

Accumulation of HIV-1 Drug Resistance Mutations After First-Line Immunological Failure to Evaluate the Options of Recycling NRTI Drugs in Second-Line Treatment: A Study from South India.

Lack of HIV-1 viral load monitoring in resource-limited settings leads to the development of HIV drug resistance mutations, although WHO recommends viral load testing for monitoring as this helps in preserving future treatment options and also avoid unnecessary switching to more expensive drugs. A total of 101 patients attaining first-line treatment failure (FTF) were followed until second-line treatment failure (STF) to study the rate of accumulation of thymidine analogue mutations (TAMs), their future drug options, and genetic evolution. The result shows that predominant nucleos(t)ide reverse transcriptase inhibitor (NRTI) mutations were M184V/I (87.3% in FTF and 79% in STF) followed by TAMs (53.4% in FTF and 54.5% in STF). The rate of accumulation of TAMs was higher for a patient with TAMI [0.015 TAM per person-month (TPPM)], TAMII (0.042 TPPM), and 1 (0.005 TPPM) or 2 TAMs (0.008 TPPM) compared with a patient with both TAMs and 3 or >3 TAMs. Future ART options show that >50% of the patients can be considered for choices to recycle NRTIs in the second-line, and third-line therapy. We conclude that the patients who initiated thymidine analogue-based first-line before 2010 can be very well opted for AZT- and TDF-based second-line regimen in the future.

Genotypic HIV-1 Drug Resistance Among Patients Failing Tenofovir-Based First-Line HAART in South India.

According to 2013 WHO guidelines, tenofovir (TDF) is the preferred first-line regimen for adults and adolescents. A total of 167 HIV-1-infected patients attaining immunological failure after TDF-based first-line HAART were included in this study, RT region of HIV-1 pol gene was sequenced for them, IAS-USA 2014 list and Stanford HIV drug resistance database were used for mutation interpretation. REGA V3.0 was used for HIV subtyping. The predominant NRTI and NNRTI mutations observed were M184IV (59.9%), K65R (28.1%), and thymidine analogue mutations (TAMs, 29.3%) and K103NS (54.5%), V106AM (39.5%), and Y181CIV (19.8%), respectively. Mutational association shows, K65R was negatively associated with TAMs (OR 0.31, p .008), M184V (OR 0.14, p .57), and K70E (OR 0.29, p .02). Genotypically predicted level of drug resistance based on mutation pattern shows 88% can be opted for azidothymidine (AZT) and still 65% can be opted for TDF. Considering the nature of K65R mutation in increasing susceptibility to AZT and its low prevalence, we conclude that in most patients failing TDF-based first-line therapy, AZT can be considered for second-line therapy followed by TDF itself.

Darunavir is a good third-line antiretroviral agent for HIV type 1-infected patients failing second-line protease inhibitor-based regimens in South India.

Eleven protease mutations have been associated with reduced susceptibility to darunavir. In this study of 87 HIV-1-infected patients experiencing virological failure to second-line regimens containing protease inhibitors boosted with ritonavir (viral load >1,000 HIV RNA copies/ml), we observed a low prevalence (3%) of ≥3 darunavir resistance-associated mutations, indicating that this drug may be a good option for third-line antiretroviral therapy in southern India.

Unusual insertion and deletion at codon 67 and 69 of HIV type 1 subtype C reverse transcriptase among first-line highly active antiretroviral treatment-failing South Indian patients: association with other resistance mutations.

We report a high frequency of drug resistance mutations among patients with unusual insertions or deletions at the ß(3)-ß(4) hairpin-loop-coding region of HIV-1 subtype C reverse transcriptase, during failure of first-line antiretroviral therapy containing only reverse transcriptase inhibitors in Chennai, India.

Viremia and HIV-1 drug resistance mutations among patients receiving second-line highly active antiretroviral therapy in Chennai, Southern India.

BACKGROUND: A cross-sectional study among individuals receiving second-line antiretroviral treatment was conducted to report on the level of detectable viremia and the types of drug resistance mutations among those with detectable human immunodeficiency virus (HIV) type 1 plasma viral loads (PVLs). METHODS: PVLs were measured using Abbott m2000rt real-time polymerase chain reaction, and genotyping was performed with the ViroSeq genotyping system, version 2.0, and ViroSeq analysis software, version 2.8. RESULTS: Of 107 patient plasma specimens consecutively analyzed, 30 (28%) had undetectable PVLs (<150 copies/mL), and 77 (72%) were viremic with a median PVL of 5450 copies/mL (interquartile range, 169-1 997 967). Sequencing was done for 107 samples with PVLs >2000 copies/mL: 33 patients (73%) had 1 of the protease (PR) inhibitor mutations; 41 (91%) had nucleoside reverse-transcriptase inhibitor (NRTI) mutations; 33 (73%) had non-NRTI (NNRTI) mutations; and 30 (66.7%) had both NRTI and NNRTI mutations. Triple-class resistance to NRTIs, NNRTIs, and PR inhibitors was observed in 24 (53%) patients. Based on the mutational profiles observed, all 45 sequences were susceptible to darunavir and tipranavir, whereas 47% showed resistance to lopinavir, 58% showed resistance to atazanavir, and >60% showed resistance to saquinavir, indinavir, nelfinavir, and fosamprenavir. CONCLUSIONS: The results of the study showed that the majority of patients receiving second-line antiretroviral therapy started to accumulate PR resistance mutations, and the mutation profiles suggest that darunavir might be the drug of choice for third-line regimens in India.