Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa

Kaleebu, Pontiano; Pillay, Deenan; Walker, A. Sarah; Robertson, Val J.; Enzama, R.; Yirrell, David; Lyagoba, Fred; Kityo, Cissy; Munderi, Paula; Reid, Andrew; Gibb, Diana; Bray, D.; Burke, Andy; Ait‐Khaled, Mounir; Muygenyi, P.; Hakim, James; Grosskurth, Heiner; Gilks, Charles F.; Tugume, S.; Chirara, Mike; Gale, Catherine V.; Mugyenyi, Peter; Ssali, Francis; Tumukunde, D.; Otim, T.; Namale, Leticia; Mukose, Aggrey; Muhwezi, Allan; Kabuye, Geoffrey; Mulindwa, G.; Atwine, Diana; Kyomugisha, Hope; Drasiku, Amos; Tumusiime, C.; Sabiiti, J.; Zawedde, C.; Komugyena, J.; Okiror, J.; Byaruhanga, Rose; Ocitti, Paul; Grace, Thomas; Katabira, H.; Barungi, G.; Masiira, D.; Atwine, A.; Murungi, S.; Tukamushaba, J.; Mugarura, Lincoln; Mwesigwa, Phyllis; Latif, A.S.; Jamu, A.; Makota, S.; Mupudzi, T.; Musoro, Godfrey; Ngorima, Nicoletta; Pascoe, Margaret; Taziwa, Fabian; Chakonza, L.; Chidziva, Ennie; Chirairo, H.; Chitsungo, S.; Mapinge, F.; Mawora, A.; Muvirimi, C.; Tinago, G.; Chimanzi, J.; Machingura, J.; Maweni, C.; Mutsai, S.; Warara, R.; Matongo, M.; Mdege, Noreen Dadirai; Mudzingwa, Shepherd; Jangano, Maureen; Machingura, Ian; Moyo, Kundai; Vere, L.; Chigwedere, E.; Phiri, Misheck Nkalo; Wangati, K.; Byomire, Helen; Amuron, Barbara; Nsibambi, D.; Kasirye, Ronnie; Zalwango, E.; Nakazibwe, M.; Kikaire, Bernard; Nassuna, G.; Massa, R.; Aber, M.; Namyalo, M.; Zalwango, Aisha; Generous, L.; Khauka, P.; Rutikarayo, N.; Nakahima, W.; Mugisha, Apollo; Nakiyingi‐Miiro, Jessica; Hughes, Peter J.; Katabira, Elly; Oyugi, Jessica H.; Ronald, Allan R.; Kambungu, A.; Martin, Jason; Nalumenya, R.; Nairubi, R.; Bulume, E.; Teopista, M.; Twijukye, C.; Sematala, F.; Byakwaga, Helen; Coutinho, Alex; Etukoit, Bernard Michael; Boocock, K.; Puddephatt, C.; Winogron, D.; Darbyshire, JH; Babiker, AG; Wilkes, H; Rauchenberger, Mary; Sheehan, S.; Peto, Leon; Taylor, Kirk A.; Weller, I. V. D.; Bahendeka, Sylver; Bassett, Mary T.; Wapakhabulo, A. Chogo; Gazzard, Brian; Mugurungi, Owen; Loeliger, Edde; Leith, J.; Naidoo, Panjasaram; Palmer, Maria; Rooney, James F.; Steens, Jean Marc; McLaren, Anya T.; Hill, Charles D.; Matenga, Jonathan; Pozniak, Anton; Serwadda, David

doi:10.1097/01.aids.0000233572.59522.45

Cited by 108 publications

(26 citation statements)

References 17 publications

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“…This prevalence is similar to some prior studies based in clinical cohorts from subtype C or mixed subtype infections, in which the K65R mutations ranged from 0 to 27% and duration on a TDF-containing regimen ranged from 324 to 1000 days (8;10;12;18–21). Notably, our results are consistent with a modest increase in K65R associated with subtype C HIV, similar to the 16% prevalence reported in a multi-national analysis of subtype C HIV (10) and with overlapping confidence intervals with another study in Africa in which 27.7% of the 47 participants receiving TDF developed the K65R mutation (12).…”

Section: Discussionsupporting

confidence: 88%

“…The 40 patients with amplified HIV RNA were all infected with subtype C HIV-1; 22 (55%) of whom had drug resistance mutations detected by population sequencing (Table 2). NNRTI mutations were the most common (21; 52%), followed by the M184V/I mutation (11, 28%; 10 with M184V and 1 with M184I). Five (12%; 95% confidence interval: 4.1–27%) patients had the K65R mutation, four of whom also had the M184V mutation.…”

Section: Resultsmentioning

confidence: 99%

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Resistance to Tenofovir-Based Regimens during Treatment Failure of Subtype C HIV-1 in South Africa

Hoffmann

Ledwaba

et al. 2013

Antiviral Therapy

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Background Tenofovir disoproxil fumarate (TDF) is increasingly available for patients infected with subtype C HIV-1. This subtype is reported to develop the principle TDF resistance mutation in the HIV reverse transcriptase, K65R, with greater propensity than other subtypes. We sought to describe K65R development during TDF use in a cohort of patients infected with subtype C HIV. Methods Using a prospectively followed cohort with 6 monthly HIV RNA assays, we identified virologic failure (defined as an HIV RNA >1000 c/mL) during treatment that included TDF. Residual serum, stored at the time of the HIV RNA assay, was used for consensus sequencing and allele-specific PCR. We assessed prevalence of resistance at failure during TDF-containing treatment and associated factors. Results Among 1,682 patients on a TDF-containing regimen, 270 developed failure of which 40 were assessed for resistance. By sequencing, the K65R was identified in 5 (12%), major NNRTI mutations in 24 (57%), and the M184V/I in 12 (28%) patients. The K65R was associated with lower HIV RNA at failure (HIV RNA log10 3.3 versus 4.2 c/mL) and prior stavudine exposure. An additional 5 patients had minority K65R populations identified by allele-specific PCR. Conclusions These data suggest that the K65R prevalence at virologic failure is moderately higher in our subtype C population than some non-subtype C HIV cohorts. However, we did not find that the K65R was highly selected in HIV-1 subtype C infected patients with up to 6 months of failure of a TDF-containing regimen.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Resistance to Tenofovir-Based Regimens during Treatment Failure of Subtype C HIV-1 in South Africa

Hoffmann

Ledwaba

et al. 2013

Antiviral Therapy

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“…In resource-limited settings male gender has been associated with later initiation of ART [60], defaulting [59], [61]-[62], non-adherence [63]-[64] and mortality [64]-[68]. The association between gender and viral suppression varies; some studies report an association between female gender and first-line viral suppression [69]-[70] others between male gender and second-line viral suppression [71], These studies are from different settings, from urban townships to rural programmes; while biological characteristics may contribute, the association with gender is likely to be influenced by societal determinants specific to each setting. Within the community programme we did not find any association between gender and second-line virological suppression, and we were unable to assess the role of gender within the workplace as the majority of patients were male.…”

Section: Discussionmentioning

confidence: 99%

Second-Line Antiretroviral Therapy in a Workplace and Community-Based Treatment Programme in South Africa: Determinants of Virological Outcome

et al. 2012

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Background: As antiretroviral treatment (ART) programmes in resource-limited settings mature, more patients are experiencing virological failure. Without resistance testing, deciding who should switch to second-line ART can be difficult. The consequences for second-line outcomes are unclear. In a workplace- and community-based multi-site programme, with 6-monthly virological monitoring, we describe outcomes and predictors of viral suppression on second-line, protease inhibitor-based ART. Methods: We used prospectively collected clinic data from patients commencing first-line ART between 1/1/03 and 31/12/08 to construct a study cohort of patients switched to second-line ART in the presence of a viral load (VL) ≥400 copies/ml. Predictors of VL<400 copies/ml within 15 months of switch were assessed using modified Poisson regression to estimate risk ratios. Results: 205 workplace patients (91.7% male; median age 43 yrs) and 212 community patients (38.7% male; median age 36 yrs) switched regimens. At switch compared to community patients, workplace patients had a longer duration of viraemia, higher VL, lower CD4 count, and higher reported non-adherence on first-line ART. Non-adherence was the reported reason for switching in a higher proportion of workplace patients. Following switch, 48.3% (workplace) and 72.0% (community) achieved VL<400, with non-adherence (17.9% vs. 1.4%) and virological rebound (35.6% vs. 13.2% with available measures) reported more commonly in the workplace programme. In adjusted analysis of the workplace programme, lower switch VL and younger age were associated with VL<400. In the community programme, shorter duration of viraemia, higher CD4 count and transfers into programme on ART were associated with VL<400. Conclusion: High levels of viral suppression on second-line ART can be, but are not always, achieved in multi-site treatment programmes with both individual- and programme-level factors influencing outcomes. Strategies to support both healthcare workers and patients during this switch period need to be evaluated; sub-optimal adherence, particularly in the workplace programme must be addressed.

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“…Triple NRTI therapy has been shown to have inferior virological and immunological outcomes and a high risk of selection for resistance mutations in ART‐naïve adult patients 89. The ARROW study showed that children on a three‐NRTI maintenance regimen with 3TC, ABC and ZDV had inferior virological outcomes at week 144 and more ZDV‐related neutropenia, but no difference in disease progression or immunological outcomes when compared to NNRTI plus 3TC and ABC 71.…”

Section: Which Art Regimen To Start As First‐line Therapymentioning

confidence: 99%

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

et al. 2015

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The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV‐1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short‐term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long‐term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first‐ and second‐line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART ‘pipeline’ of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

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Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa

Abstract: Zidovudine/lamivudine/tenofovir has good virological efficacy in advanced HIV disease. In this population, who were infected with HIV-1 subtypes A, C or D, M184V with or without NAMs was the most common route to resistance, whereas K65R was identified less often.

Cited by 108 publications

References 17 publications

Resistance to Tenofovir-Based Regimens during Treatment Failure of Subtype C HIV-1 in South Africa

Resistance to Tenofovir-Based Regimens during Treatment Failure of Subtype C HIV-1 in South Africa

Second-Line Antiretroviral Therapy in a Workplace and Community-Based Treatment Programme in South Africa: Determinants of Virological Outcome

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV‐1 infection 2015: optimizing health in preparation for adult life

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