Improved Virological Outcome in White Patients Infected With HIV-1 Non-B Subtypes Compared to Subtype B

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, Switzerland.
Clinical Infectious Diseases (Impact Factor: 8.89). 12/2011; 53(11):1143-52. DOI: 10.1093/cid/cir669
Source: PubMed

ABSTRACT Antiretroviral compounds have been predominantly studied in human immunodeficiency virus type 1 (HIV-1) subtype B, but only ~10% of infections worldwide are caused by this subtype. The analysis of the impact of different HIV subtypes on treatment outcome is important.
The effect of HIV-1 subtype B and non-B on the time to virological failure while taking combination antiretroviral therapy (cART) was analyzed. Other studies that have addressed this question were limited by the strong correlation between subtype and ethnicity. Our analysis was restricted to white patients from the Swiss HIV Cohort Study who started cART between 1996 and 2009. Cox regression models were performed; adjusted for age, sex, transmission category, first cART, baseline CD4 cell counts, and HIV RNA levels; and stratified for previous mono/dual nucleoside reverse-transcriptase inhibitor treatment.
Included in our study were 4729 patients infected with subtype B and 539 with non-B subtypes. The most prevalent non-B subtypes were CRF02_AG (23.8%), A (23.4%), C (12.8%), and CRF01_AE (12.6%). The incidence of virological failure was higher in patients with subtype B (4.3 failures/100 person-years; 95% confidence interval [CI], 4.0-4.5]) compared with non-B (1.8 failures/100 person-years; 95% CI, 1.4-2.4). Cox regression models confirmed that patients infected with non-B subtypes had a lower risk of virological failure than those infected with subtype B (univariable hazard ratio [HR], 0.39 [95% CI, .30-.52; P < .001]; multivariable HR, 0.68 [95% CI, .51-.91; P = .009]). In particular, subtypes A and CRF02_AG revealed improved outcomes (multivariable HR, 0.54 [95% CI, .29-.98] and 0.39 [95% CI, .19-.79], respectively).
Improved virological outcomes among patients infected with non-B subtypes invalidate concerns that these individuals are at a disadvantage because drugs have been designed primarily for subtype B infections.

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Available from: Huldrych F Günthard, Sep 26, 2015
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    • "Although a French study found no significant difference in the time to undetectable VL between non-B (147 days; 95% CI: 119–165) and B subtypes (168 days; 95% CI: 105–234) [31], an Italian study [32] reported a mean CD4 gain of 70 and 156 cells/ml and a mean decrease of VL in B and non-B subtypes of −0.45; −0.79 log copies/ml. The Swiss Cohort study [33] observed a low rate of virologic failure in non-B subtypes (1.4 failures/100 person-years; 95% CI: 0.9–2.1) vs. B (2.6 failures/100 person-years; 95% CI: 2.3–3.0). "
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    ABSTRACT: There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended.
    Journal of the International AIDS Society 05/2014; 17(1):18944. DOI:10.7448/IAS.17.1.18944 · 5.09 Impact Factor
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    • "In particular, even if the risk factor for HIV acquisition might be a determinant for CRT selection at time of transmission [38], it seems to lose its importance over time. A lower proportion of X4 strains has been observed among some non-B-subtypes, in particular subtype C [39], suggesting a possible association with an improved virological outcome for non-B patients when excluding racial and social variables, as recently described by some authors [40,41]; in the present study, however, non B-subtypes were rare and no definite conclusion can be drawn concerning the relationship between CRT and viral subtype. Moreover, the co-infection with other viruses, in particular with HBV and HCV, failed to demonstrate any association with CRT. "
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    ABSTRACT: Background Co-receptor tropism (CRT) in patients with a long history of HIV-1 infection and antiretroviral treatment has been rarely investigated to date. The aim of this study was to determine the prevalence of X4 and R5 strains in patients with a >15-year follow-up and to investigate the demographical, viral, immunological, clinical and therapeutic determinants of CRT in this population. The possible influence of CRT on the inflammation state related to chronic HIV infection was also examined. Methods A total of 118 HIV-1 infected patients with an initial HIV-1-positive test before 1997, and still on follow-up, were enrolled and consecutively submitted to blood sampling. Of these, 111 were on antiretroviral therapy and 89/111 (80.2%) had a plasma viral load (pVL) <25 copies/ml at testing. HIV-1 DNA was extracted and amplified from PBMCs for env gp120 sequencing. CRT was assigned by using geno2pheno and isolates were classified as X4 (FPR ≤20%) or R5 (FPR >20%). Level of serological inflammation biomarkers including IL-6, hsPCR, and D-dimers were measured. Results An X4 virus was evidenced in HIV-1 proviral DNA of 50 patients (42%) while the remaining 68 patients were classified as R5. The median follow-up was 19 years (range 15–25). No association was observed between CRT and sex, age, nationality, subtype, HIV risk factor, HBV/HCV co-infection, baseline CD4+ cell count and pVL, overall duration of antiretroviral therapy, past exposure to mono-or dual therapies, and duration of NNRTI or PI-based therapy. The presence of an X4 strain was associated with CD4 nadir (p = 0.005), CD4 absolute count over time (p < 0.001), and cumulative positive (copy/years) viremia (p <0.001) during the whole patient history. No differences were found between R5 and X4 patients regarding inflammation marker levels including Il-6, hsPCR and D-dimers. Conclusions An archived X4 virus was demonstrated in 42% of patients with a >15-year-history of HIV infection. This presence was clearly associated with a greater exposure to positive viremia and a poorer CD4 trend over time compared to R5, independent of type and duration of antiretroviral treatment. CRT does not seem to influence the inflammation rate of patients aging with HIV.
    BMC Infectious Diseases 05/2013; 13(1):220. DOI:10.1186/1471-2334-13-220 · 2.61 Impact Factor
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    • "Although HIV resistance databases continue to enter HIV genotype data from nonB subtype variants, few data sets are available to date (stanford HIV resistance database, Agence Nationale pour la Recherche sur le SIDA-France (ANRS), etc.) for drugs that have become part of first-line therapy in developed countries, for example, TDF, ATV, darunavir, ETR, and RAL. In this context as well, it is relevant that some studies have attempted to address the clinical impact of HIV diversity on treatment response as well as the limitations of such approaches [86, 87]. "
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    ABSTRACT: The vast majority of reports on drug resistance deal with subtype B infections in developed countries, and this is largely due to historical delays in access to antiretroviral therapy (ART) on a worldwide basis. This notwithstanding the concept that naturally occurring polymorphisms among different non-B subtypes can affect HIV-1 susceptibility to antiretroviral drugs (ARVs) is supported by both enzymatic and virological data. These findings suggest that such polymorphisms can affect both the magnitude of resistance conferred by some major mutations as well as the propensity to acquire certain resistance mutations, even though such differences are sometimes difficult to demonstrate in phenotypic assays. It is mandatory that tools are optimized to assure accurate measurements of drug susceptibility in non-B subtypes and to recognize that each subtype may have a distinct resistance profile and that differences in resistance pathways may also impact on cross-resistance and the choice of regimens to be used in second-line therapy. Although responsiveness to first-line therapy should not theoretically be affected by considerations of viral subtype and drug resistance, well-designed long-term longitudinal studies involving patients infected by viruses of different subtypes should be carried out.
    06/2012; 2012(4):256982. DOI:10.1155/2012/256982
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