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New HIV Drugs; Intl Drug Resistance
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Reported by Jules Levin
Feb 27, 2007
Today, there was a CROI press conference where several important resistance study reports were discussed; as well, at this press conference the principal investigators for key studies of new drugs discussed their results, including Maraviroc, MK-0518, TMC278, and the new Gilead integrase inhibitor GS9137. John Mellors hosted the press conference and highlighted the problem that like in the USA 10 years ago as we roll out HAART in developing countries HIV drug resistance is becoming a serious concern. Unlike in the USA, there is no viral load testing available to monitor patients on HAART in developing countries creating a serious problem. Therefore patients remain on failing regimens and are developing the K65R mutation creating worrisome resistance to second-line tenofovir. I asked the study investigators on these international HAART studies if they tested patients at baseline for HBV & HCV because of potential concerns regarding hepatoxicity & ALT flares. Of course I knew the answer as they said no they do not test so Mellors underscored that this was a serious concern I raised. The new drugs look very promising & Mellors said this era or this wave of new drugs was as impressive as 1996 when protease inhibitors became available. He highlighted that responses to MK0518 & Maraviroc in highly treatment experienced in these studies were in the 60-80%range for <50 copies and were as high as many of the studies in naives in early days and he is right. TMC278 also looks good in the 48 week naive study being presented here tonight in along with MK518 & Maraviroc. Below are the abstracts for the international studies reported serious concerns about resistance including for women who took single dose NVP.
Short-course Zidovudine and Lamivudine or single-dose Nevirapine-containing PMTCT Compromises 12-Month Response to HAART in African Women, Abidjan, Cote d'Ivoire (2003-2006)
P Coffie1, D Ekouevi2, M L Chaix3, B Tonwe-Gold4, S Toure4, I Viho4, C Amani-Bosse4, V Leroy1, C ROUZIOUX3, François Dabis*1, D Ekouevie1, and MTCT-Plus Initiative of ICAP
1INSERM 593, Univ Victor Segalen, Bordeaux, France; 2ANRS DITRAME PLUS Project, PACCI Collaboration, Abidjan, Cote dIvoire; 3Ctr Hosp Univ Necker, Univ Rene Descartes, Paris, France; and 4MTCT-Plus Prgm, ACONDA, Abidjan, Cote dIvoire
Background: We studied the response to HAART of women exposed to single-dose nevirapine (sdNVP) or short course zidovudine±lamivudine (ZDV±3TC) for prevention of mother-to-child transmission (PMTCT) regimens.
Methods: From a prospective cohort of the Cote d'Ivoire MTCT-Plus program, all women eligible were HIV-1 infected, had had ≥1 pregnancy, and had initiated HAART with stavudine (d4T)/ZDV, 3TC, and NVP/efavirenz (EFV). Exposed women received short course (ZDV±3TC)+sdNVP during previous pregnancy. Genotypic resistance testing was performed at week-4 post partum. Immunological failure was defined by a fall of >30% from peak CD4 count, virological failure by a plasma HIV RNA>500 copies/mL 12 months after HAART initiation. Multivariate logistic regression investigated factors associated to treatment failure.
Results: Among 247 HAART-treated women, 109 (44%) were unexposed, 81 received sc(ZDV+3TC)+sdNVP, 5 short course (ZDV+3TC), 50 short course ZDV+sdNVP, and 2 sdNVP only. No ZDV mutation was detected (n = 115); 11 of 73 (14.6%) 3TC-exposed women tested post partum had 3TC resistance mutations. Of 73 short course (ZDV+3TC)+sdNVP exposed women, 3/ (4.1%) had NVP-resistance mutations, and of 42 short course ZDV+sdNVP exposed women, 16 (38.1%) did so. HAART was initiated 19 months in median after exposure. Baseline median CD4 count was 188 cells/mm3 (IQR 126 to 264). Of 219 women, virological failure was identified in 42 (19.2%). In multivariate analysis, factors associated with virological failure were a poor self-reported adherence (adjusted odds ratio [aOR] 12.7, 95% confidence interval [CI] 3.0 to 53.9), 3TC-resistance mutations post partum (aOR 6.9, CI 1.1 to 42.9), and a baseline CD4+ count <200/mm3 (aOR 0.3, CI 0.2 to 0.8), controlling for resistance mutations / exposure to NVP, maternal age, WHO clinical stage, and hemoglobinemia. 3TC-exposed women who did not develop resistance mutations post partum were not at increased risk of virological failure (p = 0.11 in adjusted analysis). Exposure to sdNVP was not statistically associated with virological failure (aOR 1.8, CI 0.5 to 6.5 for NVP resistance; aOR 0.4, CI 0.1 to 1.4 for NVP exposure without resistance). Immunological failure was identified in 26 women of 235 (11.1%); the only associated factor was poor adherence (aOR 12.3; CI 3.2 to 47.8). Exposure to 3TC and NVP ± post-partum resistance mutations to these drugs did not predict immunological failure (p = 0.57 and 0.12, respectively in multivariate analysis), like baseline CD4+ count, WHO clinical stage, age and hemoglobinemia.
Conclusions: Short course (ZDV±3TC) and sdNVP may induce viral resistance to NVP or 3TC that can impair the subsequent women's response to HAART, an adverse phenomenon to be taken into account in PMTCT guidelines.
Emerging ART Drug Resistance in Subtype C: Experience from the 2 Clinics in Johannesburg, South Africa
Carole L Wallis*1, C Bell1, R Boulme2, I Sanne1, F Venter1, M Papathanasopoulos1, and W Stevens3
1Univ of the Witwatersrand, Johannesburg, South Africa; 2ABL SA/TherapyEdge Inc, Luxembourg, Belgium; and 3Natl Hlth Lab Svc, Johannesburg, South Africa
Background: The South African government ART roll-out program, initiated in April 2004, has enrolled >150,000 patients to date. This is the first study describing pol mutation patterns arising in patients failing either the first or second-line ART regimens from 2 Johannesburg clinics. Both clinics report an overall therapy failure rate of approximately 2% among the 10,000 patients treated to date.
Methods: Clinic 1 routinely sends samples for genotyping upon virological failure whereas clinic 2 only sends problem clinical cases due to resource constraints. Plasma from 100 patients (74 clinic 1; 26 clinic 2) was used to extract HIV RNA, protease (PR) and reverse transcriptase (RT) regions were sequenced, processed by the ViroScore database and analyzed for mutation frequencies. Subtype was designated using the Rega HIV-1 subtyping tool.
Results: Patients were on HAART regimens containing stavudine (d4T) + lamivudine (3TC) + efavirenz (EFV) or nevirapine (NVP) (85%), or zidovudine (AZT) + didanosine (ddI) + Kaletra (15%). Patients attending clinic 1 and clinic 2 had average CD4 counts of 198 and 89 cells/µL, and viral loads of 29,404 and 106,854 copies/mL, respectively. Of all patients, 68% harbored known ART drug-resistance mutations. Major RT mutations from clinic 1 were: D67N (14%), M184V (43%), K103N (28%), V106M (17%), G190A (18%). For clinic 2 they were: M41L, K65R and T215Y (12%); D67N (27%); K70R (23%); M184V (46%); K219Q (15%); K101E and G190A (12%); K103N (42%); V106M (19%); and P225H (19%). Interestingly, 22% of clinic 1 patients and 35% of clinic 2 patients had nucleoside analog mutations; 11 patients harbored primary protease inhibitors (PI) mutations (L10I, M46I, G48V, I54V, A71V, V82A, and L90M), 3 of whom were not on PI-containing regimens. A high number of secondary PR mutations were observed among all patients. Subtype analysis revealed that 97% of samples were subtype C.
Conclusions: Preliminary HIV-1 subtype C ART drug-resistance data emerging from 2 clinics in Johannesburg show mutation patterns similar to subtype B. Several important differences were noted, such as the presence of V106M, and higher prevalence rates of K65R (clinic 2), G190A and P225H (clinic 2). Thus, subtype C-specific resistance algorithms are urgently needed to avoid biased interpretation. The emergence of K65R mutations will limit the use of tenofovir (TDF) in second-line treatment. Treatment guidelines without viral load monitoring or defining treatment failure at viral load >5000copies/mL may limit second line treatment options with nucleoside analogs.
Development of Drug Resistance in a Sub-Saharan Cohort of HIV 1-infected Adult Patients Receiving Fixed-dose Combination of Stavudine + Lamivudine + Nevirapine as Standard First-line Regimen
A G Marcelin1,2, A G Marcelin1,2, B Jarrousse3, M Ba4, M Dakouo5, A Doumbia6, I Haidara6, G Brucker1,2, G Brucker1,2, G Carcelain1,2, G Carcelain1,2, C Katlama1,2, C Katlama1,2, Vincent Calvez*1,2, Vincent Calvez*1,2, and SOLTHIS Triomune study group
1Ctr Hosp Univ Pitie-Salpetriere, Paris, France; 2SOLTHIS, Paris, France; 3SOLTHIS, Ségou, Mali; 4ONG Walé, Ségou, Mali; 5ONG APROFEM, Ségou, Mali; and 6Hosp Regional, Segou, Mali
Background: Generic fixed-dose combinations are largely used in developing countries as first line regimen. As genotypic tests are not widely available in these countries, it is important to characterize the resistance patterns at failure with this kind of regimen in the perspective of second line. We report our experience of stavudine (d4T; 30 mg) + lamivudine (3TC) + nevirapine (NVP) in a program implemented by SOLTHIS in Ségou, Mali.
Methods: We included in the program 346 HIV-1-infected patients who started d4T+3TC+NVP between January 2004 and August 2005. A virological substudy was performed in 109 patients. HIV-1 plasma viral load was quantified after a minimum of 6 months of HAART. In case of viral load >200 copies/mL, resistance genotype was performed.
Results: At baseline, 93% of patients had AIDS and median CD4 count was 105 cells/mm3. Of the 109 patients, 83 (76%) had a viral load <200 copies/mL at a median time of 6.7 months after initiation. Among the 26 patients with detectable viral load (median viral load = 4150 copies/mL; range 209 to 404,000), viruses were not amplifiable in 4 cases. The 22 remaining patients harbored viruses with no mutation in 11 cases and resistance mutations in 11 cases: 1 M184V alone, 10 M184V + non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations (6 Y181C, 2 K103N, 1 V106A, and 1 G190A). No thymidine analog mutations (TAM) were observed. All sequenced viruses were CRF_02 subtype.
Conclusions: Early failures to d4T+3TC+NVP were associated in 50% of cases with no resistance mutation. The fact that >50% of the viruses harboring NNRTI mutations contained Y181C mutation in this study could be related to the use of d4T. Actually, d4T would not prevent the selection of Y181C mutation, inversely to that was observed in subtype B when zidovudine (AZT) was associated to NVP. This phenomenon can also be related to the CRF_02 subtype. It has been recently shown that HIV-1 subtype can influences the type of NVP mutation (higher frequency of Y181C for subtype A and K103N for subtype D). The absence of TAM suggests that AZT or d4T could be used in second line regimen after early failure to d4T+3TC+NVP.
Tenofovir Resistance among HIV-infected Patients Failing a Fixed-dose Combination of Stavudine + Lamivudine + Nevirapine in a Resource-limited Setting
Somnuek Sungkanuparph*1, W Manosuthi2, S Kiertiburanakul1, B Piyavong1, and W Chantratitra1
1Faculty of Med, Ramathibodi Hosp, Mahidol Univ, Bangkok, Thailand and 2Bamrasnaradura Inst, Ministry of Publ Hlth, Nonthaburi, Thailand
Background: A fixed-dose combination of stavudine (d4T) + lamivudine (3TC) + nevirapine (NVP) is extensively used in developing countries secondary to its affordable cost. Treatment failure from this regimen becomes more common and resistance testing is not widely accessible. Options for backbone in the second regimen are limited by nucleoside reverse transcriptase inhibitor (NRTI) cross resistance and the cost of abacavir and didanosine. Tenofovir (TDF) is expected to be available in Thailand in November 2006 with a low cost. Some mutation patterns after failing d4T+3TC+NVP may limit the use of tenofovir in the second regimen.
Methods: Genotypic resistance testing was conducted among HIV-infected patients who failed their initial ART regimen of a fixed-dose combination of d4T+3TC+NVP during 2003-2005. Patterns of resistance mutation contributing to tenofovir resistance were studied. Predicting factors for TDF resistance were determined from univariate and multivariate analysis.
Results: There were 98 patients with a mean (SD) age of 35.2 (6.3) years and 63% were male. Median (IQR) duration of ART was 20 (13 to 28) months. Median (IQR) CD4 cell count and HIV RNA at the time of virological failure detection was 159 (105 to 248) cells/mm3 and 4.1 (3.7 to 4.7) log copies/mL, respectively. Of the total, 10 (10.2%) patients had TDF resistance: 6 had K65R and 4 had ≥3 thymidine analog mutations (TAM) inclusive of either M41L or L210W. When categorized patients into 2 groups according to HIV RNA level at virological failure detection, the group with HIV RNA >4 log copies/mL at failure had a higher rate of tenofovir resistance when compared to the group with HIV RNA ≦4 log copies/mL at failure (20% vs 2.3%, p = 0.021). By multivariate analysis, only log HIV RNA at failure (OR 10.48; 95%CI 1.77 to 62.13, p = 0.010) and duration of ART prior to failure (OR 1.12; 95%CI, 1.03 to 1.21, p = 0.008) predicted the occurrence of tenofovir resistance.
Conclusions: TDF resistance is common among HIV-infected patients failing d4T+3TC+NVP regimen and having high HIV RNA at failure. Late detection of virological failure limits the use of tenofovir in the second regimen for patients failing d4T+3TC+NVP. In resource-limited settings where resistance testing is not widely accessible and options for the second regimen are limited, early detection of virological failure is crucial. Accessibility of HIV RNA assay for monitoring of treatment needs to be scaled-up along with accesibility of ART.
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