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Since the discovery of HIV as the causative agent of AIDS in 1983/1984, remarkable progress has been made in finding antiretroviral drugs (ARVs) that are effective against it. A major breakthrough occurred in 1996 when it was found that triple drug therapy (HAART) could durably suppress viral replication to minimal levels. It was then widely felt, however, that HAART was too expensive and complex for low- and middle-income countries, and so, with the exception of a few of these countries, such as Brazil, a massive scale-up did not begin until the WHO launched its ‘3 by 5′ initiative and sizeable funding mechanisms, such as the Global Fund to Fight AIDS, TB and Malaria and the US President's Emergency Plan for AIDS Relief (PEPFAR), came into existence. A pivotal enabler of the scale-up was a steady lowering of drug prices through entry of generic antiretrovirals, competition between generic manufacturers and the making of volume commitments. The WHO Prequalification of Medicines Programme and the Expedited Review Provision of the US Food and Drug Administration have been important for the assurance of quality standards. Antiretroviral drug development by research-based pharmaceutical companies continues, with several important innovative products, such as long-acting agents, in the pipeline.

Background There is a high incidence of tuberculosis (TB) early after antiretroviral therapy (ART) initiation. This historical cohort study evaluated the association of efavirenz (EFV) compared to nevirapine (NVP) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large, urban HIV clinic in Uganda. Methods Hazard ratios (HR) for developing TB were computed using multivariable Cox proportional hazards models with inverse weighting of the probability of being prescribed NVP or EFV (calculated by a multi-variable logistic regression model), stratifying by baseline CD4+ T-cell count. Adjustment for time-updated CD4+ T-cell count, restriction of the analysis to patients remaining in follow-up and a TB-free survival analysis were performed as sensitivity analyses. Results ART was initiated in 5,797 patients; 66% were women with a mean age of 37 years (sd 9) and a median baseline CD4+ T-cell count of 117 cells/mm3 (IQR 43–182). Overall, 60% ( n=3,484) were initiated on NVP and 40% ( n=2,313) on EFV. In the first 2 years of ART, 377 patients developed TB. The use of EFV compared to NVP was independently associated with higher TB incidence in patients with a baseline CD4+ T-cell count 3 (HR 2.05 [95% CI 1.29, 3.27]; P=0.003), but not at higher CD4+ T-cell counts (HR 0.71 [95% CI 0.39, 1.31]; P=0.428). These estimates were robust to all sensitivity analyses. Conclusions There was a higher incidence of TB in patients with baseline CD4+ T-cell counts 3 initiated on EFV compared to those initiated on NVP. Further research in a trial setting or a larger multisite observational cohort is needed to confirm these findings.

Background Therapy for chronic hepatitis B with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC) is currently recommended for HIV–HBV coinfection. However, there is limited randomized data on the efficacy of combined therapy with TDF and FTC, especially in antiretroviral (ARV)-naive patients. Methods This was a prospective randomized clinical trial comparing the efficacy of HBV monotherapy with FTC versus TDF/FTC combination therapy in ARV-naive HIV– HBV coinfection. HIV–HBV-coinfected patients initiating ARV were randomized to either FTC/zidovudine/efavirenz (EFV; n=6) or TDF/FTC/EFV ( n=10). The primary end point was the time-weighted area under the curve (TWAUC) of HBV DNA at 48 weeks. Results The median baseline CD4+ T-cell count was 64 cells/μl (interquartile range [IQR] 36–172), plasma HIV type-1 RNA was 4.90 log10 copies/ml (IQR 4.58–5.44) and plasma HBV DNA was 8.76 log10 copies/ml (IQR 8.45–8.82). A total of 11/16 (69%) patients were hepatitis B e antigen (HBeAg)-positive. The median TWAUC decrease in HBV DNA was -5.32 log10 copies/ml in the TDF/FTC group compared with -3.25 log10 copies/ml in the FTC group ( P=0.03). At week 48, 90% of the TDF/FTC group and 33% of the FTC group had plasma HBV DNAConclusions TDF/FTC combination therapy resulted in a significantly greater decrease in HBV DNA than FTC monotherapy, with a greater proportion of patients with undetectable HBV DNA at week 48. Our study supports the current recommendation of ARV containing TDF/FTC as the treatment of choice for patients with HIV–HBV coinfection.

Background Transient episodes of HIV type-1 viraemia are frequently observed in patients on suppressive combination antiretroviral therapy (cART). We studied the effect of such episodes and of treatment interruptions on clinical outcome and immunological response. Methods A total of 3,321 patients from the ATHENA cohort had virological suppression (HIV type-1 RNA400 copies/ml) viraemia and the outcomes death, AIDS or immunological response (CD4+ T-cell count increase ≥50% from 24 weeks) was studied with Poisson regression models, including either time-updated cumulative follow-up, time spent per type of episode or modelling episodes as binary status indicators. Results During 11,165 person-years of follow-up, 88 patients died, 111 developed AIDS and 2,019 had an immunological response. Longer follow-up time in treatment interruptions increased the risk of AIDS (relative risk [RR] 8.07, 95% confidence interval [CI] 3.98–16.4 per year longer) and impaired immunological response (RR 0.22, 95% CI 0.12–0.41). High-level viraemia was only associated with immunological response (RR 0.55, 95% CI 0.40–0.74), whereas low-level viraemia was not associated with any of the three outcomes. Status indicator models gave similar results. When also including time-updated CD4+ T-cell counts, the observed associations diminished. Conclusions Treatment interruptions and high-level, but not low-level, viraemia are strongly associated with clinical outcome, mainly via their effect on CD4+ T-cell counts.

HIV testing policies and practices vary widely across Europe. It is clear that there are individuals who might present late for HIV diagnosis and care within all risk groups, and potentially in any healthcare setting. This article explores the need to ensure earlier identification and treatment of late-presenting patients by reviewing strategies that might be considered. Such strategies could include routine provider-initiated HIV testing of at-risk groups in settings such as sexually transmitted infection clinics, drug dependency programmes or antenatal care. Healthcare providers might also consider routine HIV testing in all healthcare facilities, in settings including emergency and primary care, where local HIV prevalence is above a threshold that should be further evaluated. They should also take advantage of rapid testing technologies and be aware of barriers to HIV testing among specific groups to provide opportunities for testing that are relevant to local communities.

Background Nevirapine (NVP) is often prescribed once daily in clinical practice in combination with a once daily nucleoside backbone. We investigated the relationship of NVP dosing with safety and efficacy. Methods Patients from the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort study, Canadian HAART Observational Medical Evaluation and Research (HOMER) cohort and Swiss HIV Cohort Study (SHCS) using NVP-based combination therapy either once daily or twice daily were included. Risk factors for discontinuing NVP because of hypersensitivity reactions (HSRs) were investigated using multivariate logistic regression. Risk factors for virological failure 96 weeks after NVP initiation were identified using logistic regression and Cox models. Results Of 5,636 patients (774 once daily and 4,862 twice daily), 268 (4.8%) discontinued NVP because of HSR between 2 and 18 weeks. Logistic regression showed that, compared with patients with detectable HIV type-1 (HIV-1) RNA starting twice-daily NVP, there was a significantly higher risk of discontinuation of once-daily NVP because of HSR in patients with detectable HIV-1 RNA at the start of NVP (odds ratio [OR] 1.52; P=0.04), whereas the risk was actually significantly lower in patients starting once-daily NVP with undetectable HIV-1 RNA (OR 0.44; P=0.04). Cox models showed that risk of virological failure was not different for twice- versus once-daily NVP in treatment-naive patients (twice-daily versus once-daily hazard ratio [HR] 1.01; P=0.95), treatment- experienced patients experiencing treatment failure (twice-daily versus once-daily HR 1.22; P=0.30) or patients with undetectable HIV-1 RNA simplifying treatment with NVP (twice-daily versus once-daily HR 1.29; P=0.30). Conclusions Initiation of a once-daily NVP-based regimen in patients with suppressed viraemia carries a low risk of treatment-limiting HSR. Once- or twice-daily NVP-based regimens appear to have similar antiretroviral efficacy.

BackgroundThe pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood.MethodsRelationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively.ResultsRitonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks).ConclusionsReduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each - to varying degrees - associated with various metabolic disturbances.

In this study we investigated the long-term effect of highly active antiretroviral therapy (HAART) on HIV-specific CD4+T-cell responses in comparison with virus-specific CD4+T-cell responses against the persistent herpes viruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). To this end, HIV- and herpes virus-specific cellular immune responses were measured longitudinally in 10 seroconverters with long-term follow-up including 55 months of successful suppression of viral load by HAART. HIV- and CMV-specific CD4+T cells producing interferon-γ (IFNγ) or interleukin-2 (IL-2) were analysed as well as proliferative capacity. EBV-specific CD4+T cells were determined using a 12-day ex vivo assay. Initiation of HAART resulted in a transient increase of HIV-specific IL-2+IFNγ+CD4+T cells and, to a lesser extent, IL-2+CD4+T cells. Long-term HAART resulted in an increase in HIV-, CMV- and EBV-specific CD4+T-cell proliferative capacity. The increase in HIV- and herpes-virus-specific CD4+T-cell proliferative capacity after 55 months of HAART suggests that the improved proliferative response is not specific for HIV, but reflects a more general improvement of antiviral immune responses, which is induced by HAART.

Objectives In countries with high numbers of HIV/tuberculosis coinfection nevirapine and rifampin are used extensively. However, limited data are available about whether or not nevirapine and rifampin can be safely coadministered without the plasma concentration of nevirapine falling below therapeutic levels. Methods Blood samples for determination of nevirapine plasma concentrations were collected from patients using nevirapine 200 mg twice daily with or without concomitant rifampin. Bivariate and multivariate linear regression models were used to investigate factors possibly related to nevirapine concentrations. Results We received 74 blood samples from patients using nevirapine plus rifampin, and collected blood samples from an equal number of controls using nevirapine only. Groups were similar for age, gender, weight, height and body mass index (BMI). In the rifampin group the mean nevirapine concentration was 5.47 ±2.66mg/l, whereas in the control group the mean nevirapine concentration was 8.72 ±3.98 mg/l. In the rifampin group seven nevirapine trough concentrations were low (Conclusion Although nevirapine plasma concentrations were 3.3 mg/l lower when co-administered with rifampin, still more than 86% of these patients had nevirapine plasma concentrations >3.1 mg/l. Our results suggest that from a pharmacological point of view the majority of Thai coinfected patients, who have low BMIs, reach nevirapine plasma concentrations that are adequate for treatment of HIV. However this can only be undertaken if nevirapine plasma concentration monitoring is available and can be closely followed.

Objective To evaluate CD4 cell count-driven strategies for the initiation of highly active antiretroviral therapy (HAART) in terms of the reduction of the incidence of AIDS-defining events in resource-poor settings. Methods Data from the Amsterdam Cohort Study on HIV infection and AIDS were used to estimate the hazard of AIDS in untreated HIV-1 infection and after initiation of HAART, respectively, conditional on CD4 cell count. Different strategies for initiating therapy were compared by calculating the expected HAART administration rate and 1-year cumulative AIDS incidence in three different population settings, varying in the stage of HIV-1 infection at the time of presentation. Results Among 695 HIV-1-infected cohort participants, the 1-year AIDS incidence density (ID) ranged from 3.2 per 100 person-years for CD4 cell counts 600–700 cells/mm3, to 31.9 per 100 person-years for CD4 cell counts 100–200 cells/mm3 and 77.9 per 100 person-years for CD4 cell counts below 100 cells/mm3. Upon initiation of HAART, the ID in the lowest CD4 strata declined to 13.3 and 16.3 per 100 person-years, respectively. Extrapolated to developing countries, supply of HAART to patients presenting with HIV-1 infection below 200 CD4 cells/mm3 is expected to give an administration rate of 67%, while the AIDS incidence will drop from over 30% to almost 10%. Conclusions Introduction of HAART in populations with advanced HIV-1 infection can accomplish a threefold reduction of the AIDS incidence when HAART is administered to patients with CD4 cell counts below 200 cells/mm3. In a hospital-based setting in resource-poor environments this ensures an efficient treatment allocation.

Objective The pharmacokinetics of 800 mg and 1200 mg of saquinavir soft-gel caps (SQV-SGC) twice daily plus 100 mg itraconazole once daily were compared to 1400 mg SQV-SGC twice daily without itraconazole. Methods The pharmacokinetics of SQV were determined in 17 randomly selected patients on 1400 mg twice daily SQV-SGC without itraconazole and after 2 weeks with lower SQV-SGC doses plus itraconazole. SQV plasma concentrations were determined by HPLC. Pharmacokinetic parameters were calculated by a non-compartmental model. Results Median (+IQR) area under plasma concentration-versus-time curve (AUC0–12h) were 3.33 (1.96–7.34), 4.29 (3.14–7.67) and 4.07 (2.76–4.49) mg/l.h for SQV 1400 mg without itraconazole, SQV 1200 mg with itraconazole and SQV 800 mg with itraconazole, respectively. These differences were not statistically significant. The median Cmin was above the proposed minimum effective concentration of 0.05 mg/l for all three regimens. Conclusion SQV-SGC 800 mg or 1200 mg twice daily boosted with 100 mg of itraconazole once daily resulted in adequate SQV pharmacokinetics not significantly different from SQV-SGC 1400 mg twice daily.

Starting standard antiretroviral therapy within 10 days after the onset of a primary HIV-1 infection cannot prevent the establishment of a reservoir of HIV-1-infected memory CD4 T cells. Here we studied the reservoir of HIV-1-infected memory CD4 T cells in four patients who started a triple class, five-drug regimen during primary HIV-1 infection. There was a strong correlation between the proportion of productively infected CD4 HLA-DR- T lymphocytes and plasma HIV-1 RNA levels (r=0.852; P- T lymphocytes was reduced below the level of quantification. In the fourth patient the cellular reservoir remained quantifiable. In two patients who stopped therapy 44 weeks after initiation an immediate rebound of the plasma HIV-1 RNA level and the proportion of productively infected CD4 HLA-DR– T lymphocytes occurred. In conclusion, initiation of a potent five-drug, triple class regimen during primary HIV-1 infection does not result in virus-specific immune control upon discontinuation of therapy after 44 weeks. Therefore, longer or even stronger suppression of viral replication might be necessary to achieve this goal in primary HIV-1 infection.

Background Vitamin D insufficiency plays an important role in the development of fibrosis in chronic liver disease. Methods This was a cross-sectional study from Thailand. Liver fibrosis was assessed by transient elastography. Serum 25 hydroxyvitamin D (25[OH]D)Results A total of 158 HIV–HBV-coinfected patients (32% female, median age 43 years) were included. Overall, liver disease was mild with 13.4% having a fibrosis score (FS) of 7.1–14 kPa and 2% with a FS>14 kPa. Median (IQR) duration on TDF was 5 years (4–7). The median estimated glomerular filtration rate was 96.9 ml/min/1.73 m2. The median (IQR) serum 25(OH)D levels prior to and following TDF were 24.8 ng/ml (21.3–30.6) and 22.8 ng/ml (18.0–27.7), respectively; P≤0.001). The proportion of patients with hypovitaminosis D significantly increased from 72.2% (95% CI 64.7, 78.6) prior to TDF to 84.2% (95% CI 77.7, 89.0) after taking TDF ( P=0.01). Factors associated with hypovitaminosis D by multivariate analysis were female sex (adjusted OR 3.8, 95% CI 1.1, 13.7; P=0.038) and duration of antiretroviral therapy (ART)>5 years (OR 3.3, 95% CI 1.2, 8.8; P=0.017). Vitamin D levels were not associated with significant liver fibrosis. Conclusions Although our HIV–HBV-coinfected patients live in the tropics, there was a high prevalence of hypovitaminosis D, especially in female patients and those receiving prolonged ART. Since HIV–HBV-coinfection requires long-term use of the HBV-active drug, TDF, which can also contribute to bone loss, routine vitamin D assessment and supplementation as necessary should be considered.

Background Generic products reduce the costs of HIV treatment. Few generic second-line antiretroviral products are available. We assessed pharmacokinetics, safety and efficacy of generic lopinavir/ritonavir (LPV/r) produced by the Government Pharmaceutical Organization (GPO) of Thailand in Thai HIV-infected adults. Methods This was a single-arm prospective study. Patients with plasma HIV-1 RNAmin) of the different formulations. Plasma HIV-1 RNA and safety were assessed until week 48. Results A total of 70 patients (32 males) were enrolled. Mean (sd) age was 40.7 (7.9) years and mean (sd) body weight was 60.3 (9.0) kg. Before study entry, all patients were virologically suppressed using a PI-based regimen; 62 (88.6%) were using LPV/r (Kaletra® SGC n=22 and Mylan generic tablets n=40). Mean (sd) Cmin of GPO lopinavir and GPO ritonavir at week 4 were 7.1 (2.9) mg/l and 0.39 (0.21) mg/l, respectively, and not significantly different from the Cmin when taking Kaletra® SGC or Mylan generic tablets. After 48 weeks, 95.6% of patients maintained plasma HIV-1 RNAConclusions Generic LPV/r showed adequate levels, good tolerability and excellent 48-week efficacy.

In this study we investigated the long-term effect of highly active antiretroviral therapy (HAART) on HIV-specific CD4+ T-cell responses in comparison with virus-specific CD4+ T-cell responses against the persistent herpes viruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV). To this end, HIV- and herpes virus-specific cellular immune responses were measured longitudinally in 10 seroconverters with long-term follow-up including 55 months of successful suppression of viral load by HAART. HIV- and CMV-specific CD4+ T cells producing interferon-gamma (IFNgamma) or interleukin-2 (IL-2) were analysed as well as proliferative capacity. EBV-specific CD4+ T cells were determined using a 12-day ex vivo assay. Initiation of HAART resulted in a transient increase of HIV-specific IL-2(+)IFNgamma(+)CD4(+) T cells and, to a lesser extent, IL-2(+)CD4(+) T cells. Long-term HAART resulted in an increase in HIV-, CMV- and EBV-specific CD4+ T-cell proliferative capacity. The increase in HIV- and herpes-virus-specific CD4+ T-cell proliferative capacity after 55 months of HAART suggests that the improved proliferative response is not specific for HIV, but reflects a more general improvement of antiviral immune responses, which is induced by HAART.

The relationships between adverse events (AEs) and plasma concentrations of nevirapine (NVP) and efavirenz (EFV) were investigated as part of the large, international, randomized 2NN study.Treatment-naive, HIV-1-infected patients received NVP (once or twice daily), EFV or their combination, each in combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Concentrations of NVP and EFV were quantitatively assessed by a validated HPLC assay. Individual Bayesian estimates of the area under the plasma concentration-time curve over 24 h (AUC24h), and minimum and maximum plasma concentrations (Cmin and Cmax) as measures for drug exposure of NVP and EFV, were generated using a previously developed population pharmacokinetic model. Pharmacokinetic parameters were compared for patients with and without central nervous system (CNS) and psychiatric AEs, hepatic events, liver enzyme elevations (LEEs) and rash. Furthermore, it was investigated whether a clear cut-off for a pharmacokinetic parameter could be identified above which the incidence of AEs was clearly increased. AEs were also related to demographic parameters and baseline characteristics.In total, from 1077 patients, NVP (3024 samples) and EFV (1694 samples) plasma concentrations and AE data (825 observations) were available. For all patients Cmin, Cmax and AUC24h were determined. When corrected for known covariates of gender, CD4 cell count at baseline, region, hepatitis coinfection and possible interactions between these factors, no significant associations between AEs and any tested exposure parameter of NVP was observed. Also, no target Cmin value, above which patients were at increased risk for AEs, could be established. On the other hand, geographical region, hepatitis coinfection, CD4 cell count and gender were found to be significantly related with the incidence of CNS and psychiatric AEs, hepatic events, LEEs and rash during the treatment with NVP. The occurrence of elevated liver enzymes during the first 6 weeks in the EFV-containing arm was significantly (P = 0.036) correlated to the exposure of EFV (Cmin). Only hepatitis coinfection impacted on LEEs during the first 6 weeks of treatment. With an EFV Cmin above 2.18 mg/l during the induction phase, patients were 4.4 (range 1.3-15.5) times more at risk for elevated liver enzymes. No other correlations between AEs and EFV pharmacokinetics or patient characteristics could be identified.Pharmacokinetic parameters of NVP did not have a relationship to AEs in the 2NN trial when corrected for known covariates. The value of periodical drug monitoring of NVP as a way to prevent toxicity is therefore limited. Treating physicians should instead focus on factors that are more predictive of AEs (gender, CD4 count and hepatitis coinfection). High EFV Cmin levels resulted in elevated liver enzyme values during the first 6 weeks of treatment. Regular measurement of EFV levels and liver enzymes at the start of therapy may therefore be advised.

Objective To assess whether differences in safety profiles between nevirapine (NVP) and efavirenz (EFV), as observed in the 2NN study, translated into differences in ‘health related quality of life’ (HRQoL). Design A sub-study of the 2NN study, with antiretro-viral-naive patients randomly allocated to NVP (once or twice daily), EFV or NVP+EFV, in addition to stavudine and lamivudine. Methods Comparing differences in changes of HRQoL over 48 weeks as measured with the Medical Outcomes Study HIV Health Survey (MOS-HIV) questionnaire, using analysis of variance. Results The 2NN study enrolled 1216 patients. No validated questionnaires were available for 244 patients, and 55 patients had no HRQoL data at all, leaving 917 patients eligible for this sub-study. A total of 471 (51%) had HRQoL measurements both at baseline and week 48. The majority (69%) of patients without HRQoL measurements did, however, complete the study. The change in the physical health score (PHS) was 3.9 for NVP, 3.4 for EFV and 2.4 for NVP+EFV ( P=0.712). For the mental health score (MHS) these values were 6.1, 7.0 and 3.9, respectively ( P=0.098). A baseline plasma HIV-1 RNA concentration (pVL) ≥100 000 copies/ml and a decline in pVL (per log10) were independently associated with an increase of PHS. An increase of MHS was only associated with pVL decline. Patients experiencing an adverse event during follow-up had a comparable change in PHS but a significantly smaller change in MHS, compared with those without an adverse event. Conclusions First-line ART containing NVP and/or EFV leads to an improvement in HRQoL. The gain in HRQoL was similar for NVP and EFV, but slightly lower for the combination of these drugs.

Introduction Mitochondrial toxicity resulting from mitochondrial DNA (mtDNA) depletion is suggested to be involved in the pathogenesis of lipodystrophy. Methods We cross-sectionally assessed lipodystrophy both clinically and radiographically in patients who, 4 years before, had been enrolled in a randomized comparative trial of stavudine- or zidovudine-based therapy. mtDNA content was measured in peripheral blood mononuclear cells (PBMCs) and subcutaneous adipose tissue from the thigh and back. Results Twenty-eight of the 45 patients enrolled in the original trial were included. Despite comparable exposure to stavudine or zidovudine (51 and 50 months, respectively), lipoatrophy prevalence by intent-to-treat analysis was significantly greater in stavudine recipients (82 vs 9%, P=0.0001). Likewise, those allocated to stavudine had significantly less peripheral fat. In an analysis restricted to patients who had remained on randomly allocated nucleoside reverse transcriptase inhibitors (NRTIs), mtDNA in PBMCs decreased after the start of treatment in both groups ( PDiscussion This study objectively confirms that regimens containing stavudine are associated with a greater risk of lipoatrophy than those containing zidovudine. mtDNA in PBMCs markedly declined with both treatments and was lowest in patients with lipoatrophy. The lack of difference in mtDNA in adipose tissue from patients with as opposed to without lipoatrophy may have been masked by a relative preponderance of stromal and vascular tissue in the subcutaneous tissue samples from these patients, combined with compensatory mitochondrial proliferation in remaining adipocytes. However, our findings may also suggest that the different risk of lipoatrophy observed between NRTIs cannot solely be explained by differences in mtDNA depletion directly at the level of peripheral adipose tissue.

Starting standard antiretroviral therapy within 10 days after the onset of a primary HIV-1 infection cannot prevent the establishment of a reservoir of HIV-1-infected memory CD4 T cells. Here we studied the reservoir of HIV-1-infected memory CD4 T cells in four patients who started a triple class, five-drug regimen during primary HIV-1 infection. There was a strong correlation between the proportion of productively infected CD4 HLA-DR- T lymphocytes and plasma HIV-1 RNA levels (r=0.852; P0.001) during the first 24 weeks of therapy. Within 45 weeks of treatment, in three of the four patients the proportion of productively infected CD4 HLA-DR- T lymphocytes was reduced below the level of quantification. In the fourth patient the cellular reservoir remained quantifiable. In two patients who stopped therapy 44 weeks after initiation an immediate rebound of the plasma HIV-1 RNA level and the proportion of productively infected CD4 HLA-DR- T lymphocytes occurred. In conclusion, initiation of a potent five-drug, triple class regimen during primary HIV-1 infection does not result in virus-specific immune control upon discontinuation of therapy after 44 weeks. Therefore, longer or even stronger suppression of viral replication might be necessary to achieve this goal in primary HIV-1 infection.

To evaluate CD4 cell count-driven strategies for the initiation of highly active antiretroviral therapy (HAART) in terms of the reduction of the incidence of AIDS-defining events in resource-poor settings.Data from the Amsterdam Cohort Study on HIV infection and AIDS were used to estimate the hazard of AIDS in untreated HIV-1 infection and after initiation of HAART, respectively, conditional on CD4 cell count. Different strategies for initiating therapy were compared by calculating the expected HAART administration rate and 1-year cumulative AIDS incidence in three different population settings, varying in the stage of HIV-1 infection at the time of presentation.Among 695 HIV-1-infected cohort participants, the 1-year AIDS incidence density (ID) ranged from 3.2 per 100 person-years for CD4 cell counts 600-700 cells/mm3, to 31.9 per 100 person-years for CD4 cell counts 100-200 cells/mm3 and 77.9 per 100 person-years for CD4 cell counts below 100 cells/mm3. Upon initiation of HAART, the ID in the lowest CD4 strata declined to 13.3 and 16.3 per 100 person-years, respectively. Extrapolated to developing countries, supply of HAART to patients presenting with HIV-1 infection below 200 CD4 cells/mm3 is expected to give an administration rate of 67%, while the AIDS incidence will drop from over 30% to almost 10%.Introduction of HAART in populations with advanced HIV-1 infection can accomplish a threefold reduction of the AIDS incidence when HAART is administered to patients with CD4 cell counts below 200 cells/mm3. In a hospital-based setting in resource-poor environments this ensures an efficient treatment allocation.

During sustained suppression of plasma viraemia using a standard triple-drug regimen, replication-competent HIV-1 can still be recovered from resting memory CD4 T cells. In an attempt to accelerate the clearance of this pool of infected CD4 T cells, eight antiretroviral therapy-naive HIV-1-infected patients were treated with a five-drug regimen. While plasma HIV-1 RNA levels generally remained below the level of detection (5 copies/ml), replication competent HIV-1 was isolated from HLA-DR- CD4 T cells from all patients on multiple occasions throughout treatment. Decay slopes of infected CD4 T cells ranged from -0.061/week (half-life=2.6 months) to +0.003/week (half-life = infinite). Virus was still detectable at the last time point analysed (80-173 weeks) in all patients. Although more intensive treatment results in improved suppression of plasma viraemia compared with standard drug regimens, it does not result in clearance of the viral reservoir in this timeframe. Strategies other than treatment with a combination of five of the currently available drugs need to be pursued in order to achieve eradication of HIV-1 from this cellular reservoir.