Basic science
Weiser B, Philpott S, Klimkait T, Burger H, Kitchen C, Burgisser P, Gorgievsk M, Perrin L, Piffaretti JC, Ledergerber B, the Swiss HIV Cohort Study. HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy. AIDS 2008; 22(4):469-479.
Although combination antiretroviral therapy dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. Weiser and colleagues aimed to investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. From the Swiss HIV Cohort Study, 96 participants who initiated combination antiretroviral therapy yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/[mu]l; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. In conclusion, HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during combination antiretroviral therapy, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.
Editors’ note: HIV-1 requires two receptors to infect cells: CD4 is the primary receptor, with chemokine receptors CCR5 and CXCR4 serving as co-receptors. CCR5 using viruses (called R5 viruses) are those most commonly transmitted between people but after years of infection CXCR4-using strains (X4 viruses) are detected in half of people living with HIV and often predict CD4 cell depletion and accelerated disease progression. This study suggests that an assay detecting a high fraction of viruses using the X4 coreceptor early in the course of infection could be clinically useful; clinical trials are now needed to evaluate whether early treatment of asymptomatic people with CD4 counts above 350 cells/µl who harbor X4 strains can reduce HIV-1 levels and slow disease progression.
Vitezica, Zulma G; Milpied, Brigitte; Lonjou, Christine; Borot, Nicolas; Ledger, Terence Niel; Lefebvre, Anne; Hovnanian, Alain. HLA-DRB1*01 associated with cutaneous hypersensitivity induced by nevirapine and efavirenz. AIDS 2008;22(4):540-541.
HLA typing, demographic and immunological risk factors for nevirapine and efavirenz reactions were studied in a French cohort of HIV patients. Cases with isolated rash were significantly associated with HLA-DRB1*01 allele. No liver toxicity was observed and no association was detected with the percentage of CD4 T-cells. This study suggests that HLA-DRB1*01 allele plays an important role in susceptibility to cutaneous reactions associated with nevirapine and efavirenz in HIV patients.
Editors’ note: Being able to detect which patients are more likely to develop rashes with the first line non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs nevirapine (NVP) and efavirenz (EFV) would be very useful clinically. Between 20-35% of patients on nevirapine and 32% of patients on efavirenz develop cutaneous hypersensitivity reactions within 6 weeks of treatment initiation and need to be switched to other drugs. This small study of 21 patients should be confirmed and, although its findings are promising, there is a way to go before genetic screening of human leukocyte antigen (HLA) markers to detect such susceptibility can be turned into a diagnostic test which would help decrease or eliminate this problem.
Boberg A, Isaguliants M Vaccination against drug resistance in HIV infection. Expert Rev Vaccines. 2008;7(1):131-45.
HIV-1 resistance to currently employed antiretroviral drugs and drug-associated adverse reactions and toxicity point to a need for additional measures to control HIV-1 replication in HIV-infected patients. The immune system of HIV-infected individuals mount an immune response against the regions harboring drug-resistance mutations, sometimes stronger than that against the parental wild-type sequences. A potent cross-reactive immune response against drug-resistant pol proteins can suppress the replication of drug-escaping HIV. This suggests the possibility for a vaccination against existing and anticipated drug-resistant HIV variants. If successful, therapeutic vaccines against drug resistance would ease the therapeutic modalities and limit the spread of drug-resistant HIV. A better understanding of the complex interactions between patterns of drug-resistance mutations, immune responses against these mutations and their antigen presentation by particular human lymphocyte antigen alleles could help to tailor these vaccines after new drugs/new mutations. In this review, we describe the developments in the field of immunization against mutations conferring drug resistance and evaluate their prospects for human vaccination.
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