Effect of HIV‐1 Subtype on Virologic and Immunologic Response to Starting Highly Active Antiretroviral Therapy

Geretti, Anna María; Harrison, Linda; Green, Hannah; Sabin, Caroline; Hill, Teresa; Fearnhill, Esther; Pillay, Deenan; Dunn, David

doi:10.1086/598502

Cited by 137 publications

(112 citation statements)

References 36 publications

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“…These results were also limited by the inability of bulk sequencing technology to detect low-frequency variants that had been shown to affect treatment outcomes, [48][49][50][51][52][53] and that patients with HPLC-MS/ MS detectable pretherapy plasma drug levels were included in all virologic outcome analyses because HPLC-MS/MS was not performed on plasma samples with wildtype viruses. Our results agreed with reports that subtype-D infection was not associated with a worse virologic outcome, 54,55 which implied that the observed difference in suppression was not biased by subtype differences.…”

Section: Discussionsupporting

confidence: 92%

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

Lee

Bangsberg

Muzoora

et al. 2014

AIDS Research and Human Retroviruses

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Few reports have examined the impact of HIV-1 transmitted drug resistance (TDR) in resource-limited settings where there are fewer regimen choices and limited pretherapy/posttherapy resistance testing. In this study, we examined TDR prevalence in Kampala and Mbarara, Uganda and assessed its virologic consequences after antiretroviral therapy initiation. We sequenced the HIV-1 protease/reverse transcriptase from n = 81 and n = 491 treatment-naive participants of the Uganda AIDS Rural Treatment Outcomes (UARTO) pilot study in Kampala (AMU 2002(AMU -2004 and main cohort in Mbarara (MBA 2005(MBA -2010. TDR-associated mutations were defined by the WHO 2009 surveillance mutation list. Posttreatment viral load data were available for both populations. Overall TDR prevalence was 7% (Kampala) and 3% (Mbarara) with no significant time trend. There was a slight but statistically nonsignificant trend indicating that the presence of TDR was associated with a worse treatment outcome. Virologic suppression (£ 400 copies/ml within 6 months posttherapy initiation) was achieved in 87% and 96% of participants with wildtype viruses versus 67% and 83% of participants with TDR (AMU, MBA p = 0.2 and 0.1); time to suppression (log-rank p = 0.3 and p = 0.05). Overall, 85% and 96% of study participants achieved suppression regardless of TDR status. Surprisingly, among the TDR cases, approximately half still achieved suppression; the presence of pretherapy K103N while on nevirapine and fewer active drugs in the first regimen were most often observed with failures. The majority of patients benefited from the local HIV care system even without resistance monitoring. Overall, TDR prevalence was relatively low and its presence did not always imply treatment failure.

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Section: Discussionsupporting

confidence: 92%

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

Lee

Bangsberg

Muzoora

et al. 2014

AIDS Research and Human Retroviruses

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“…This high rate of virological success is in agreement with recently obtained findings [21,28], and confirms that these results are consistent with an accurate viral load monitoring (as shown by the high number of viraemia measurements) and an appropriate use of new drugs and new regimens in the framework of good clinical practice. It should be highlighted that all patients analysed in this study started their first-line regimen based on genotypic resistance testing; indeed, even if approximately 10% of the overall population has been infected by a resistant virus, the probability of achieving virological response at any time was similar in patients with transmitted drug resistance (and treated with resistance test-driven therapy) in comparison with those infected by a wild-type virus (data not shown).…”

Section: Discussionsupporting

confidence: 92%

Impact of Pre-Therapy Viral Load on Virological Response to Modern First-Line Haart

et al. 2013

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Background: We tested whether pre-HAART viraemia affects the achievement and maintenance of virological success in HIV-1-infected patients starting modern firstline therapies. Methods: A total of 1,430 patients starting their first HAART (genotype-tailored) in 2008 (median; IQR: 2006-2009) were grouped according to levels of pre-HAART viraemia (≤30,000, 30,001-100,000, 100,001-300,000, 300,001-500,000 and >500,000 copies/ml). The impact of pre-therapy viraemia on the time to virological success (viraemia ≤50 copies/ml) and on the time to virological rebound (first of two consecutive viraemia values >50 copies/ml after virological success) were evaluated by Kaplan-Meier curves and Cox regression analyses. Results: Median pre-HAART viraemia was 5.1 log 10 copies/ml (IQR 4.5-5.5), and 53% of patients had viraemia >100,000 copies/ml. By week 48, the prevalence of patients reaching virological success was >90% in all pre-HAART viraemia ranges, with the only exception of range >500,000 copies/ml (virological success =83%; P<0.001). Higher pre-HAART viraemia was tightly correlated with longer median time to achieve virological success. Cox multivariable estimates confirmed this result: patients with pre-HAART viraemia >500,000 copies/ml showed the lowest hazard of virological undetectability after adjusting for age, gender, pre-HAART CD4 + T-cell count, transmitted drug resistance, calendar year and third drug administered (adjusted hazard ratio [95% CI]: 0.27 [0.21, 0.35]; P<0.001). Pre-HAART viraemia >500,000 copies/ml was also associated with higher probability of virological rebound compared with patients belonging to lower viraemia strata at weeks 4, 12 and 24 (P=0.050). Conclusions: At the time of modern HAART, and even though an average >90% of virological success, high pre-HAART viraemia remains an independent factor associated with delayed and decreased virological success. Patients starting HAART with >500,000 copies/ml represent a significant population that may deserve special attention.HAART has significantly extended the time to development of AIDS and to death in HIV-infected individuals [1,2]. Its efficacy in suppression of plasma HIV-1 RNA to undetectable levels, and in increasing CD4 + T-cell count, is well documented in several clinical trials [3][4][5][6].Despite years of great progress in treating AIDS, however, in some patients starting their first treatment; the effectiveness of HAART is still not sufficient, with consequent virological failures [7][8][9]. These failures can be caused by several factors, such as drug potency, drug

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“…4,5 Different HIV-1 subtypes exhibit differences in frequency and route of virus transmission, in the pathogenesis of the disease as well as in the kinetics and mechanisms of drug resistance development, thus potentially affecting HIV-1 disease management. 3,6,7 In view of the above, we aimed to investigate key resistance mutations in the reverse transcriptase (RT) and protease genes following ART rollout in a rural setting in Ifakara, Tanzania.…”

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confidence: 99%

Prevalence of Drug Resistance Mutations and HIV Type 1 Subtypes in an HIV Type 1-Infected Cohort in Rural Tanzania

Masimba

Kituma

Klimkait

et al. 2013

AIDS Research and Human Retroviruses

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The development of resistance mutations in drug-targeted HIV-1 genes compromises the success of antiretroviral therapy (ART) programs. Genotyping of these mutations enables adjusted therapeutic decisions both at the individual and population level. We investigated over time the prevalence of HIV-1 primary drug resistance mutations in treatment-naive patients and described the HIV-1 subtype distribution in a cohort in rural Tanzania at the beginning of the ART rollout in 2005-2007 and later in 2009. Viral RNA was analyzed in 387 baseline plasma samples from treatment-naive patients over a period of 5 years. The reverse transcriptase (RT) and protease genes were reversely transcribed, polymerase chain reaction (PCR) amplified, and directly sequenced to identify HIV-1 subtypes and single nucleotide polymorphisms associated with drug resistance (DR-SNPs). The prevalence of major DR-SNPs in 2005-2007 in the RT gene was determined: K103N (5.0%), Y181C (2.5%), M184V (2.5%), and G190A (1.7%), and M41L, K65KR, K70KR, and L74LV (0.8%). In samples from 2009 only K103N (3.3%), M184V, and T215FY (0.8%) were detected. Initial frequencies of subtypes C, A, D, and recombinants were 43%, 32%, 18%, and 7%, respectively. Later similar frequencies were found except for the recombinants, which were found twice as often (15%), highlighting the subtype diversity and a relatively stable subtype frequency in the area. DR-SNPs were found at initiation of the cohort despite very low previous ART use in the area. Statistically, frequencies of major mutations did not change significantly over the studied 5-year interval. These mutations could reflect primary resistances and may indicate a possible risk for treatment failure.

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Effect of HIV‐1 Subtype on Virologic and Immunologic Response to Starting Highly Active Antiretroviral Therapy

Abstract: Patients infected with prevalent non-B subtypes were as likely to achieve viral load suppression as persons infected with subtype B and showed comparable rates of CD4 cell count recovery. HAART achieves excellent outcomes regardless of the infecting subtype.

Cited by 137 publications

References 36 publications

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

Prevalence and Virologic Consequences of Transmitted HIV-1 Drug Resistance in Uganda

Impact of Pre-Therapy Viral Load on Virological Response to Modern First-Line Haart

Prevalence of Drug Resistance Mutations and HIV Type 1 Subtypes in an HIV Type 1-Infected Cohort in Rural Tanzania

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