Improved adipose tissue function with initiation of protease inhibitor-only ART.

OBJECTIVES: Use of ART containing HIV PIs has previously been associated with toxicity in subcutaneous adipose tissue (SAT), potentially contributing to the development of lipodystrophy and insulin resistance. However, the effect of PIs on SAT function in ART-naive patients independent of other ART classes is unknown. This study aimed to elucidate the effect of initiating PI-only ART on SAT function in ART-naive subjects. METHODS: In the HIVNAT-019 study, 48 HIV-infected, ART-naive Thai adults commencing PI-only ART comprising lopinavir/ritonavir/saquinavir for 24 weeks underwent assessments of fasting metabolic parameters and body composition. In a molecular substudy, 20 subjects underwent SAT biopsies at weeks 0, 2 and 24 for transcriptional, protein, mitochondrial DNA (mtDNA) and histological analyses. ClinicalTrials.gov registration number: NCT00400738. RESULTS: Over 24 weeks, limb fat increased (+416.4 g, P = 0.023), coinciding with larger adipocytes as indicated by decreased adipocyte density in biopsies (-32.3 cells/mm2, P = 0.047) and increased mRNA expression of adipogenesis regulator PPARG at week 2 (+58.1%, P = 0.003). Increases in mtDNA over 24 weeks (+600 copies/cell, P = 0.041), decreased NRF1 mRNA expression at week 2 (-33.7%, P < 0.001) and increased COX2/COX4 protein ratio at week 24 (+288%, P = 0.038) indicated improved mitochondrial function. Despite decreased AKT2 mRNA at week 2 (-28.6%, P = 0.002) and increased PTPN1 mRNA at week 24 (+50.3%, P = 0.016) suggesting insulin resistance, clinical insulin sensitivity [by homeostasis model assessment (HOMA-IR)] was unchanged. CONCLUSIONS: Initiation of PI-only ART showed little evidence of SAT toxicity, the changes observed being consistent with a return to health rather than contributing to lipodystrophy.

Global response to HIV: treatment as prevention, or treatment for treatment?

The concept of "treatment as prevention" has emerged as a means to curb the global HIV epidemic. There is, however, still ongoing debate about the evidence on when to start antiretroviral therapy in resource-poor settings. Critics have brought forward multiple arguments against a "test and treat" approach, including the potential burden of such a strategy on weak health systems and a presumed lack of scientific support for individual patient benefit of early treatment initiation. In this article, we highlight the societal and individual advantages of treatment as prevention in resource-poor settings. We argue that the available evidence renders the discussion on when to start antiretroviral therapy unnecessary and that, instead, efforts should be aimed at offering treatment as soon as possible.

Advanced liver fibrosis by transient elastography, fibrosis 4, and alanine aminotransferase/platelet ratio index among Asian hepatitis C with and without human immunodeficiency virus infection: role of vitamin D levels.

BACKGROUND AND AIM: Vitamin D insufficiency plays an important role in liver fibrosis in hepatitis C virus (HCV)-infected patients. We assessed liver fibrosis by transient elastography and 25 hydroxy vitamin D [25(OH)D] status in HCV-infected patients, with (HIV/HCV) or without HIV co-infection (HCV) from Thailand. METHODS: Fibrosis stage was defined as mild (< 7.1 kPa); moderate (7.2-9.4 kPa); severe (9.5-14 kPa), and cirrhosis (> 14 kPa). Hypovitaminosis D was defined as 25(OH)D < 30 ng/mL. Logistic regression analyses were used to assess predictors for significant fibrosis. Serum 25(OH) D levels, HCV genotypes (GT), interleukin-28B (IL28B) and HCV-RNA were assessed. RESULTS: A total of 331 HCV and 130 HIV/HCV patients were enrolled (70% male, 35% people who inject drugs [PWIDs]). HCV GT distribution was as follows: GT3 47%, GT1 34%, GT6 17%. IL-28B CC genotype (rs12979860) were found in 88% of HIV/HCV and 85% of HCV. In HCV, liver fibrosis was mild in 56.5%; moderate in 18.4%; severe in 12.4%; and cirrhosis in 12.7%. In HIV/HCV, these figures were 30.6%, 27.8%, 17.6%, and 24.1%, respectively. Patients with significant fibrosis were more often male, older, with HIV infection, hypovitaminosis D, and less likely to be infected with GT6. Factors associated with significant fibrosis by multivariate analysis were HIV infection (adjusted odd ratio [95% confidential interval]: 2.67, 1.20-5.93), P = 0.016, Fib-4 score > 1.45 (6.30, 2.70-14.74), P < 0.001, and hypovitaminosis D (2.48, 1.09-5.67), P = 0.031. GT 6 was less likely to have advanced liver fibrosis (0.17, 0.05-0.65), P = 0.01. CONCLUSIONS: HIV infection, Fib-4 score > 1.45, and hypovitaminosis D are strong and independent predictors for the presence of advanced fibrosis in our HCV-infected patients. These data highlight the urgent need of HCV treatment and vitamin D supplement in resource-limited settings.

No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial.

BACKGROUND: The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI). METHODS AND FINDINGS: Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1∶1∶1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1∶1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count < 350 cells/mm(3) or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log(10) copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log(10) copies/ml in the 24- and 60-wk treatment arms (between groups: p < 0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0-1.8) y compared to 3.0 (1.9-4.2) and 1.8 (0.5-3.0) y in the 24- and 60-wk treatment arms (log rank test, p < 0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25-0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32-0.95]) were associated with time to (re)start of cART. CONCLUSIONS: In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection.

Unrecognised tuberculosis at antiretroviral therapy initiation is associated with lower CD4+ T cell recovery.

OBJECTIVES: To investigate whether an unrecognised diagnosis of tuberculosis (TB) at the start of antiretroviral therapy (ART) influences subsequent CD4+ T cell (CD4) count recovery in an urban HIV clinic in Uganda. METHODS: In a retrospective cohort study, a multivariable polynomial mixed effects model was used to estimate CD4 recovery in the first 96 weeks of ART in two groups of patients: prevalent TB (started ART while on TB treatment), unrecognised TB (developed TB within 6 months after start ART). RESULTS: Included were 511 patients with a median baseline CD4 count of 57 cells/mm(3) (interquartile range: 22-130), of whom 368 (72%) had prevalent TB and 143 (28%) had unrecognised TB. Compared with prevalent TB, unrecognised TB was associated with lower CD4 count recovery at 96 weeks: -22.3 cells/mm(3) (95% confidence interval -43.2 to -1.5, P = 0.036). These estimates were adjusted for gender, age, baseline CD4 count and the use of zidovudine-based regimen. CONCLUSIONS: Unrecognised TB at the time of ART initiation resulted in impaired CD4 recovery compared with TB treated before ART initiation. More vigilant screening with more sensitive and rapid TB diagnostics prior to ART initiation is needed to decrease the risk of ART-associated TB and sub-optimal immune reconstitution.

Long-term voluntary counseling and testing (VCT) uptake dynamics in a multicountry HIV workplace program in sub-Saharan Africa.

High uptake of HIV voluntary counseling and testing (VCT) services is important for the success of HIV workplace programs in sub-Saharan Africa. From 2001 onwards, Heineken, a multinational brewing company, implemented a comprehensive HIV prevention and treatment program for employees and their dependents of its African subsidiaries. Confidential in-house VCT is part of this program. VCT uptake dynamics over time, and factors associated with early uptake were studied. Between September 2001 and December 2007, 9723 adult beneficiaries were tested for HIV in 14 company sites in five African countries. Three hundred and seventy (3.8%) of tested persons were infected with HIV-1. During the first 12 months 1412 tests were done, compared to 8311 tests in the subsequent years. The annual average uptake of testing among eligible persons varied between 15 and 32%. The coverage was higher among female compared to male employees, and higher among female compared to male spouses. Distinct peaks in uptake were linked to specific local events. HIV-1 infected persons were significantly more likely to be tested in the early period. The proportion of HIV-1 infected persons among testees was 8.8% in the first 12 months compared to 3.0% in the subsequent period (p<0.001). HIV-1 infected persons diagnosed in the early period were in a more advanced clinical stage, and had a significantly lower CD4 count than those tested later (median CD4 count 227 vs. 314 cells/microl; p=0.002). In this workplace program, HIV-1 infected individuals came earlier for an HIV test than uninfected people, and people with advanced infection came earlier than those with less advanced disease. Employees' spouses are harder to reach than employees and extra efforts should be undertaken to reach them as well. Uptake of HIV testing can be actively influenced by educational or promotional activities.

Mortality and morbidity among HIV type-1-infected patients during the first 5 years of a multicountry HIV workplace programme in Africa.

BACKGROUND: This study aimed to evaluate the effectiveness of an HIV workplace programme in sub-Saharan Africa. METHODS: The international brewing company, Heineken, introduced an HIV workplace programme in its African subsidiaries in 2001. Beneficiaries from 16 sites in 5 countries were eligible. HIV type-1 (HIV-1)-infected individuals were assessed clinically and immunologically, and started highly active antiretroviral therapy (HAART) if they had AIDS or had a CD4+ T-cell count <300 cells/microl. In this cohort, study patients were followed-up for vital status, new AIDS events, CD4+ T-cell count and haemoglobin. RESULTS: Over the first 5 years of the programme, 431 adults were found to be HIV-1-infected. The mortality rate among those not yet taking HAART was 2.6 per 100 person-years of observation (pyo). By October 2006, 249 patients had started HAART at a median CD4+ T-cell count of 170 cells/microl; 59 (23.7%) patients were in CDC stage C. Among patients on HAART, 25 died and 7 were lost to follow-up. The mortality rate was 3.7 per 100 pyo overall, 14 per 100 pyo in the first 16 weeks and 2.5 per 100 pyo thereafter (P < 0.0001). At 4 years after start of treatment, 89% of patients were known to be alive. The CD4+ T-cell count increased by a median of 153 and 238 cells/microl after 1 and 4 years of HAART, respectively. CONCLUSIONS: In this HIV workplace programme in sub-Saharan Africa, long-term high survival was achieved.

Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA cohort study.

BACKGROUND: Recommendations that nevirapine (NVP) should be avoided in female individuals with CD4 cell counts >250 cells/microL and in male individuals with CD4 cell counts >400 cells/microL are based on findings in treatment-naive patients. It is unclear whether these guidelines also apply to treatment-experienced patients switching to NVP-based combination therapy. METHODS: Patients in the ATHENA cohort study who had used NVP-based combination therapy were included. We identified patients who discontinued NVP-based combination therapy because of hypersensitivity reactions (HSRs; rash and/or hepatotoxicity) within 18 weeks after starting such therapy. We grouped patients according to their CD4 cell count at the start of NVP-based combination therapy (current CD4 cell count) as having a high CD4 cell count (for female patients, >250 cells/microL; for male patients, >400 cells/microL) or a low CD4 cell count. Treatment-experienced patients were further subdivided according to the last available CD4 cell count before first receipt of antiretroviral therapy (ART; pre-ART CD4 cell count) using the same criteria. Risk factors for HSR were assessed using multivariate logistic regression. RESULTS: Of 3752 patients receiving NVP-based combination therapy, 231 patients (6.2%) discontinued NVP therapy because of HSRs. Independent risk factors included female sex and Asian ethnicity. Having an undetectable viral load (VL) at the start of NVP therapy was associated with reduced risk of developing an HSR (adjusted odds ratio [OR], 0.52; 95% confidence interval [CI], 0.38-0.71). Pretreated patients with low pre-ART and high current CD4 cell counts and a detectable VL when switching to NVP-based combination therapy had a significantly higher risk of developing an HSR, compared with treatment-naive patients who started NVP therapy with low CD4 cell counts (adjusted OR, 1.87; 95% CI, 1.11-3.12); pretreated patients with low pre-ART CD4 cell counts who switched to NVP therapy with a high current CD4 cell count and an undetectable VL did not have an increased risk of developing an HSR (adjusted OR, 1.03; 95% CI, 0.66-1.61). CONCLUSIONS: Treatment-experienced patients who start NVP-based combination therapy with low pre-ART and high current CD4 cell counts and an undetectable VL have a similar likelihood for discontinuing NVP therapy because of HSRs, compared with treatment-naive patients with low CD4 cell counts. This suggests that NVP-based combination therapy may be safely initiated in such patients. However, in similar patients with a detectable VL, it is prudent to continue to adhere to current CD4 cell count thresholds.

Ketoconazole is inferior to ritonavir as an alternative booster for saquinavir in a once daily regimen in Thai HIV-1 infected patients.

OBJECTIVE: To improve the pharmacokinetics of protease inhibitors, boosting with low-dose ritonavir is performed. However, toxicity, storage conditions and high costs of antiretroviral treatment may necessitate interruption of ritonavir. Ketoconazole was investigated as a potential booster of once-daily (o.d.) saquinavir. METHODS: In a single-group, two-period design, 25 virologically and immunologically stable patients on saquinavir/ritonavir 2000/100 mg o.d. were switched to saquinavir/ketoconazole 2000/400 mg o.d. for 2 weeks. Two steady-state pharmacokinetic curves were recorded at both periods. RESULTS: Fourteen females and 11 male patients were included. Median age was 34 years [interquartile range (IQR), 32-42 years], body weight 54 kg (IQR, 47-59 kg) and body mass index 21 kg/m (19-23 kg/m). The mean saquinavir area under the curve (AUC) during boosting with ritonavir was 57.93 +/- 27.96 mg/h/l, maximum observed concentration (Cmax) was 7.50 +/- 3.45 mg/l and concentration at 24 h (Cmin) was 0.35 +/- 0.30 mg/l. When ketoconazole was used, the saquinavir AUC, Cmax, and Cmin were 12.00 +/- 6.97 mg/h/l, 2.43 +/- 1.35 mg/l and 0.03 +/- 0.04 mg/l, respectively. CONCLUSION: Boosting with ketoconazole resulted in 80% lower exposure to saquinavir. Although saquinavir AUC might still be adequate for treatment, concentrations at 24 h reached levels below the recommended trough concentrations of 0.1 mg/l, which may result in selection of resistant HIV-1 viral strains. Therefore, boosting of saquinavir by ketoconazole is not recommended.

Intravenous immunoglobulin (IVIG) treatment for modulation of immune activation in human immunodeficiency virus type 1 infected therapy-naive individuals.

We evaluated the ability of intravenous immunoglobulin (IVIG) to diminish immune hyperactivation, which is considered a major cause of CD4+ T cell loss during chronic HIV-1 infection and whether this affected CD4+ T cell counts and plasma HIV-1 RNA (pVL). Therefore, we treated six chronically HIV-1-infected, antiretroviral-therapy-naive patients with IVIG (0.4 g/kg) at weeks 0 and 4, with a follow-up of 12 weeks after the second dosage during which pVL, T cell numbers, and T cell activation were measured. At baseline median CD4+ T cell counts were 300 (range 200-460) x 10(6)/liter and median pVL was 5.0 (range 3.2-5.2) log10 copies/ml. IgG plasma levels peaked during the first days after administration. We observed a decrease in the percentage of activated (CD38+ HLA-DR+) CD4+ and CD8+ T cells [3.5% (range 1-7%) and 5% (1-10%), respectively (p = 0.027)], but no effect on the fraction of proliferating CD4+ or CD8+ T cells as measured by Ki67 expression. CD4+ T cell counts were significantly increased on day 4 (median +55 cells, range 0-150, p = 0.043). pVL was significantly increased on day 1 after IVIG infusion (median +0.13 log10, range 0.01-0.55, p = 0.028). All these parameters returned to baseline levels within 1 week after infusion. In conclusion, administration of IVIG caused a temporary decrease in T cell activation and an increase in CD4+ T cell counts, despite an increase in pVL. Our results support the hypothesis that T cell activation, rather than direct HIV-1 infection, mediates the loss of CD4+ T cells and suggest that immunomodulating therapy in HIV-1 infection could indeed be effective.

Antiviral activity of HIV type 1 protease inhibitors nelfinavir and indinavir in vivo is not influenced by P-glycoprotein activity on CD4+ T cells.

P-glycoprotein (P-gp) can compromise the antiretroviral effect of a protease inhibitor (PI)-containing regimen for HIV-1, but can also reduce HIV-1 replication. We studied the net effect of P-gp on the intracellular HIV-1 RNA and DNA load in vivo. CD4(+) T cells were isolated from 27 HIV-1 patients (13 without and 14 with a PI-containing regimen) and subsequently sorted in CD45RO(-) (naive) and CD45RO(+) (memory) subsets with either high (P-gp(high)) or low (P-gp(low)) P-gp activity. Unspliced HIV-1 RNA and HIV-1 DNA load were determined. For each patient P-gp(high) and P-gp(low) subsets were compared. In patients on a PI-containing regimen, intracellular unspliced HIV-1 RNA was significantly lower in P-gp(high)-naive CD4(+) cells compared to P-gp(low)-naive CD4(+) cells (p = 0.04). The same trend was seen in naive CD4(+) cells of treatment naive patients. In both treated and untreated patients HIV-1 DNA levels were significantly lower in P-gp(high) than in P-gp(low) memory CD4(+) cells (p = 0.02 and p = 0.04). High cellular P-gp activity coincided with a reduced intracellular HIV-1 load in vivo, both in therapy-naive and in PI-treated patients. Therefore we conclude that the potential efflux function of P-gp on PIs may be clinically less relevant than the effect of P-gp on intracellular HIV-1 replication.

Stavudine but not didanosine as part of HAART contributes to peripheral lipoatrophy: a substudy from the Antiretroviral Regimen Evaluation Study (ARES).

PURPOSE: To objectively assess changes in body fat distribution in a subgroup of antiretroviral therapy-naïve participants in a randomized comparative trial of regimens including a nucleoside analogue backbone of didanosine with either lamivudine or stavudine. METHOD: Whole body dual-energy X-ray absorptiometry (DEXA) scans were performed at baseline and weeks 48 and 96 of therapy in all 19 patients from one of the sites participating in the Antiretroviral Regimen Evaluation Study (ARES). Patients had been randomized to receive nelfinavir/didanosine/stavudine (n = 8), nevirapine/didanosine/lamivudine (n = 7), or ritonavir-boosted saquinavir/didanosine/lamivudine (n = 4). RESULTS: In an intent-to-treat analysis, patients allocated to didanosine plus stavudine-containing treatment after 96 weeks had lost a median of 1,825 g (-26%) of total limb fat, as compared to a median gain of 1,639 (48%) and 403 (6%) g in those randomized to the didanosine/lamivudine plus nevirapine or saquinavir-containing regimens, respectively. These changes in limb fat were statistically significantly different when comparing patients allocated to stavudine-containing treatment with both of the other two treatment arms combined (p = .01). CONCLUSION: This study suggests that didanosine/lamivudine, when combined with either nevirapine or ritonavir-boosted saquinavir over 96 weeks of therapy, is possibly not associated with limb fat atrophy, in contrast to when treatment contained didanosine, stavudine, and nelfinavir combined.

Dyslipidemia in an Asian population after treatment for two years with protease inhibitor-containing regimens.

There are limited data about dyslipidemia in Asian patients treated with combination antiretroviral therapy. To assess the relative association of different protease-inhibitor-containing regimens with the degree of dyslipidemia, fasting lipid levels were compared during 110 weeks in 250 nucleoside-experienced but protease-inhibitor-naïve Thai patients beginning treatment with 5 protease-inhibitor-containing regimens. Regimens were (1) stavudine, didanosine, and saquinavir; (2) zidovudine, lamivudine, and saquinavir; (3) zidovudine, lamivudine, and indinavir; (4) zidovudine, lamivudine, and ritonavir-boosted indinavir; and (5) efavirenz and ritonavir-boosted indinavir. Triglyceride levels were available for all patients; total cholesterol and high-densitylipoprotein cholesterol levels were available for patients receiving indinavir. The strongest predictors of dyslipidemia after beginning protease-inhibitor-based therapy were treatment regimen and baseline dyslipidemia. Triglycerides, total cholesterol, and high-density-lipoprotein cholesterol changes from baseline to week 110 were significant in patients taking ritonavir-boosted indinavir. Efavirenz and ritonavir-boosted indinavir were associated with significant high-density-lipoprotein cholesterol increases compared with other regimens. Non-stavudine-containing non-boosted protease-inhibitor-based highly active antiretroviral treatment regimens had the least association with dyslipidemia.

Viral dynamics after starting first-line HAART in HIV-1-infected children.

BACKGROUND: After starting HAART, the plasma HIV-1 RNA (pVL) declines rapidly to undetectable levels in most treated adults and children. The viral dynamics in children are assumed to differ from those in adults. Therefore viral decay and time to reach a pVL of < 400 copies/ml during the first weeks after starting HAART were studied in a cohort of HIV-1-infected children. METHODS: Viral decay expressed as half-life and time to reach a pVL of < 400 copies/ml in 39 HIV-1-infected children starting HAART were calculated and correlated with age, pretreatment with antiretroviral mono- or duo-therapy, and baseline pVL. RESULTS: Baseline pVL correlated with age (r, -0.41; P = 0.01). Median half-life of the virus was 2.1 days (interquartile range, 1.8-3.0 days). No correlation was found between the half-life of the virus and the baseline pVL at the start of treatment, antiretroviral pretreatment or age. Eight children did not reach a pVL of < 400 copies/ml with the first allocated medication regimen. These children were significantly younger than those in whom HIV was successfully suppressed (P = 0.009). The remaining 31 children reached a pVL of < 400 copies/ml in a median of 8.1 weeks after the start of therapy; time to reach a pVL of < 400 copies/ml was only correlated with baseline pVL. CONCLUSIONS: These results suggest that pVL at baseline correlated with age. HAART was able to suppress pVL below the lower limit of detection in children with a viral decay rate of 2.1 days, similar to adults and irrespective of baseline pVL.

Long-term highly active antiretroviral therapy in chronic HIV-1 infection: evidence for reconstitution of antiviral immunity.

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.

No virological failure in semen during properly suppressive antiretroviral therapy despite subtherapeutic local drug concentrations.

PURPOSE: The aim of the study was to investigate whether drug resistance occurs earlier in seminal than in blood plasma with the use of such HAART regimens, of which only the two NRTIs achieve therapeutic concentrations in seminal plasma. METHOD: Seminal and blood plasma of 12 patients, for 48-96 weeks on suppressive first-line therapy with saquinavir/ritonavir/didanosine/lamivudine, nelfinavir/didanosine/stavudine, or efavirenz/lamivudine/zidovudine were prospectively evaluated for HIV-1-RNA resistance mutations and drug concentrations. RESULTS: Saquinavir, nelfinavir, and efavirenz blood plasma concentrations were in the therapeutic range. Nelfinavir and efavirenz seminal plasma concentrations were below the limit of quantification. In only 2 of 9 seminal plasma samples, from 1 of 6 patients, the saquinavir concentration was above the minimum therapeutic level. The seminal plasma HIV-1-RNA concentration remained undetectable in all patients up to 96 weeks, and therefore drug resistance could not be demonstrated. Thus, despite suboptimal local drug concentrations, no virological failure occurred in seminal plasma after prolonged first-line HAART. CONCLUSION: This finding supports the hypothesis that the source of HIV in semen is a spillover from the blood/extraluminal tissue and that therefore seminal plasma drug levels may not be critical for viral suppression within the lumen of the male genital tract.

HIV disease progression in a patient cohort treated via a clinical research network in a resource limited setting.

OBJECTIVE: To examine HIV disease progression in a cohort of adult patients treated with antiretroviral therapy (ART) via a clinical research network in Thailand. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A cohort of 417 patients enrolled in a series of randomized ART trials, between 1996 and December 2002. MAIN OUTCOME MEASURES: Progression to combined endpoint of AIDS defining illness or death according to baseline characteristics, ART used, immunological and virological responses to initial 6 months of ART. RESULTS: During 1677 person years of follow-up, 29 of 417 patients progressed; tuberculosis was the most common event defining progression (14 of 29 events). The rates of progression to combined endpoint or death alone were 1.7 [95% confidence interval (CI), 1.1-2.4] and 0.7 (95% CI, 0.3-1.3) per 10 person years respectively. Compared to patients with baseline CD4 cell counts > or =350 x 10/l, the adjusted hazard ratio (HR) for progression was 3.67 (95% CI, 1.31-10.27) for patients with <200 x 10 cells/l. Responses to 6 months of therapy were the strongest predictors of disease progression; compared to patients with undetectable viral load at 6 months, HR for progression was 4.95 (95% CI, 2.14-11.46) for viral load >4 log10. Compared to patients with a 6-month CD4 cell count > or =350 x 10/l, HR for progression was 5.22 (95% CI, 1.90-14.37) for patients with <200 x 10 cells/l. CONCLUSIONS: HIV-infected patients in Thailand who had access to ART, appropriate care, CD4 cell and viral load monitoring facilities via a clinical research network had progression rates comparable to those in developed countries. In this setting, ART initiation could generally be delayed until the CD4 cell count approaches 200 x 10/l.

Analysis of the effect of highly active antiretroviral therapy during acute HIV-1 infection on HIV-specific CD4 T cell functions.

BACKGROUND: It has been reported that antiretroviral therapy (HAART) during acute HIV-1 infection may rescue HIV-1-specific CD4 T cell responses. OBJECTIVE: To determine the duration of this preserved response by investigating the long-term effects of HAART during acute infection on HIV-specific CD4 T cell function related to possible immune control during subsequent therapy interruption. METHODS: A longitudinal analysis followed HIV-specific CD4 T cell reactivity in 17 individuals with well-documented acute HIV-1 infection where five out of 11 HAART-treated patients stopped therapy and six were untreated. Peripheral blood mononuclear cells were stimulated with overlapping peptide pools derived from Gag and Nef. Production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) by CD4 T cells was analysed together with proliferative responses. RESULTS: Absolute numbers, but not percentages, of Gag-specific IFN-gamma-, IL-2- or IFN-gamma/IL-2-producing CD4 T cells were increased in treated compared with untreated individuals up to 2 years after seroconversion. HAART during acute HIV-1 infection was associated with lower viral load but did not result in increased proliferation of HIV-specific CD4 T cells. One out of five individuals who discontinued therapy showed evidence for immune control. However, patients who failed to control viraemia also had measurable proliferative HIV-specific CD4 T cell responses and preserved numbers of cytokine-producing CD4 T cells. CONCLUSIONS: Early HAART during acute HIV-1 infection resulted in higher numbers of HIV-specific IFN-gamma- and IL-2-producing CD4 T cells, but this preservation in four out of five patients was not associated with control of viraemia upon treatment interruption.