Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial.

BACKGROUND: Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1. However, the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown. We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96%. We aimed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes. METHODS: The HPTN 052 trial is a randomised controlled trial done at 13 sites in nine countries. We enrolled HIV-1-serodiscordant couples to the study and randomly allocated them to either early or delayed antiretroviral treatment by use of permuted block randomisation, stratified by site. Random assignment was unblinded. The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study (early treatment group) or after a decline in CD4 count or with onset of an AIDS-related illness (delayed treatment group). Primary events were AIDS clinical events (WHO stage 4 HIV-1 disease, tuberculosis, and severe bacterial infections) and the following serious medical conditions unrelated to AIDS: serious cardiovascular or vascular disease, serious liver disease, end-stage renal disease, new-onset diabetes mellitus, and non-AIDS malignant disease. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00074581. FINDINGS: 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group (two individuals were excluded from this group after randomisation). Median CD4 counts at randomisation were 442 (IQR 373-522) cells per µL in patients assigned to the early treatment group and 428 (357-522) cells per µL in those allocated delayed antiretroviral treatment. In the delayed group, antiretroviral treatment was initiated at a median CD4 count of 230 (IQR 197-249) cells per µL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment (hazard ratio 0·73, 95% CI 0·52-1·03; p=0·074). New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation (0·64, 0·43-0·96; p=0·031), tuberculosis developed in 17 versus 34 patients, respectively (0·49, 0·28-0·89, p=0·018), and primary non-AIDS events were rare (12 in the early group vs nine with delayed treatment). In total, 498 primary and secondary outcomes occurred in the early treatment group (incidence 24·9 per 100 person-years, 95% CI 22·5-27·5) versus 585 in the delayed treatment group (29·2 per 100 person-years, 26·5-32·1; p=0·025). 26 people died, 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group. INTERPRETATION: Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes. The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment. FUNDING: US National Institute of Allergy and Infectious Diseases.

Clinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission.

OBJECTIVE: Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4. We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and human immunodeficiency virus type 1 (HIV-1) drug resistance mutations in pregnant women following single-dose intrapartum nevirapine. METHODS: In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor and were randomly assigned to receive lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir for 7 or 21 days. Plasma nevirapine level was quantified on postpartum day 1 and on weeks 1, 3, and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters, including elimination constant, time to protein-adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine level below the quantification limit. RESULTS: Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and random assignment to receive lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T → C (P = .004) but not with CYP2B6 516G → T (P = .8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G → T (P = .04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype. CONCLUSIONS: The effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T → C than for 516G → T and are less pronounced than at steady state.

Isolated cortical blindness without simultaneous neurological involvement in progressive multifocal leukoencephalopathy in a patient with human immune deficiency virus infection.

BACKGROUND: This is a case report of cortical blindness in a HIV-positive patient with progressive multifocal leukoencephalopathy (PML) without any other associated neurological dysfunction. FINDINGS: Young HIV-positive patient presented to us with sudden profound visual loss. On examination and further investigation, we have diagnosed cortical blindness without any other focal neurological deficit due to PML. CONCLUSION: Our case highlights the fact that PML needs to be suspected in patients with HIV, presenting with cortical blindness even without any other focal neurological defect.

Ocular lesions in 1,000 consecutive HIV-positive patients in India: a long-term study.

BACKGROUND: Ocular lesions in patients on highly active antiretroviral therapy (HAART) have shown changes in disease prevalence and pattern. Although they have been described in the Western population, there are not many such studies in the HAART era from India. This study aims to present the clinical profile, systemic correlation, and visual outcome in HIV-positive patients in relation to HAART in comparison with pre-HAART Indian studies and current Western data. Ocular findings and systemic correlation in 1,000 consecutive patients with HIV seen at a tertiary eye care center were analyzed. This study uses a prospective observational case series design. RESULTS: Age range of the patients was 1.5 to 75 years. Ocular lesions were seen in 68.5% of the patients (cytomegalovirus (CMV) retinitis was the commonest). The commonest systemic disease was pulmonary TB. Mean interval between HIV diagnosis and onset of ocular lesions was 2.43 years. CD4 counts range from 2 to 1,110 cells/mm3. Immune recovery uveitis (IRU) was seen in 17.4%. Interval between HAART initiation and IRU was 4 months to 2.5 years. Recurrence of ocular infection was seen in 2.53% (post-HAART) and > 20% (pre-HAART). Overall visual outcome showed improvement in about 14.3% and was maintained in 71.6% of the patients. CONCLUSIONS: CMV retinitis is the commonest ocular opportunistic infection in India, even in the HAART era. Newer manifestations of known diseases and newer ocular lesions are being seen. In contrast to Western studies, in our patients on HAART, ocular lesions do not always behave as in immunocompetent individuals. Ocular TB needs to be kept in mind in India, as well as other neuro-ophthalmic manifestations related to cryptococci, especially in gravely ill patients. Occurrence and frequency of various ocular opportunistic infections in developing nations such as India have significant variations from those reported in Western literature and need to be managed accordingly.

An inexpensive, simple, and manual method of CD4 T-cell quantitation in HIV-infected individuals for use in developing countries.

CD4+ T lymphocytes are currently the most common surrogate marker indicating immune status and disease progression with HIV infection. The cost of monitoring disease progression and response to therapy is still prohibitively expensive. Flow cytometry is the gold standard for the estimation of CD4+, but the high initial investment for this technology and expensive reagents makes it unaffordable for developing countries like India. We evaluated the Coulter cytosphere assay for quantifying CD4+ T lymphocytes in comparison with the standard method, flow cytometry, in 122 HIV-infected individuals. The correlation coefficient of the cytosphere assay compared with that of flow cytometry for CD4+ T lymphocytes was 0.97 (P< 0.0001), with a confidence interval of 0.95 to 0.98. The sensitivity, specificity, positive predictive value, and negative predictive value of the cytosphere assay in enumerating absolute CD4+ T-lymphocyte counts of less than 200/microL were 94.9%, 96.4%, 92.5%, and 97.6%, respectively. This is a simple inexpensive method and has a strong correlation with flow cytometry. Hence, the cytosphere assay can be an alternate to flow cytometry for the estimation of CD4+ T-lymphocyte counts, especially in resource-poor settings of developing countries, for monitoring HIV progression and response to therapy.