Praphan Phanuphak

Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study

BACKGROUND The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. METHODS In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. FINDINGS Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. INTERPRETATION Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.

HIV/AIDS in Asia

HIV (ie, HIV-1) epidemics in Asia show great diversity, both in severity and timing. But epidemics in Asia are far from over and several countries including China, Indonesia, and Vietnam have growing epidemics. Several factors affect the rate and magnitude of growth of HIV prevalence, but two of the most important are the size of the sex worker population and the frequency with which commercial sex occurs. In view of the present state of knowledge, even countries with low prevalence of infection might still have epidemics affecting a small percentage of the population. Once HIV infection has become established, growing needs for care and treatment are unavoidable and even the so-called prevention-successful countries of Thailand and Cambodia are seeing burgeoning care needs. The manifestations of HIV disease in the region are discussed with the aim of identifying key issues in medical management and care of HIV/AIDS. In particular, issues relevant to developing appropriate highly active antiretroviral treatment programmes in the region are discussed. Although access to antiretroviral therapy is increasing globally, making it work effectively while simultaneously expanding prevention programmes to stem the flow of new infections remains a real challenge in Asia. Genuine political interest and commitment are essential foundations for success, demanding advocacy at all levels to drive policy, mobilise sufficient resources, and take effective action.

Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results

Objective: To compare the efficiency and safety of atazanavir and nelfinavir in antiretroviral-naive patients. Design: Randomization to atazanavir 400 mg or 600 mg once daily; nelfinavir 1250 mg twice a day, plus lamivudine and stavudine. Methods: A blinded (to the atazanavir dose), 48-week trial in patients with HIV-1 RNA ⩾ 2000 copies/ml, CD4 cell count ⩾ 100 × 106cells/l. Primary end-point: change in HIV-1 RNA from baseline at 48 weeks. Secondary end-point: subjects with HIV-1 RNA < 400, and < 50 copies/ml, CD4 cell count changes, adverse events. Results: The 467 randomized subjects had comparable baseline characteristics across treatments. With atazanavir 400 mg, 600 mg and nelfinavir, respectively, mean changes in HIV-1 RNA (log10 copies/ml) from baseline to 48 weeks were −2.51, −2.58, −2.31; HIV-1 RNA < 400 copies/ml [intent-to-treat population (ITT), non-completion = failure (NC = F)], 64%, 67%, 53%; HIV-1 RNA < 50 copies/ml (ITT NC = F), 35%, 36%, 34%; mean CD4 cell count increased comparably at 48 weeks (234 × 106, 243 × 106, 211 × 106cells/l). Adverse events were similar across treatments with the exception of diarrhea (more frequent with nelfinavir) and jaundice (more frequent with atazanavir). Mean changes from baseline to 48 weeks were: fasting low density lipoprotein cholesterol, +5.2%, +7.1% and +23.2% (at 56 weeks) and fasting triglycerides (48 weeks), +7.2%, +7.6% and +49.5%, in the atazanavir 400 mg, 600 mg, and nelfinavir groups, respectively (P < 0.01, atazanavir versus nelfinavir). Conclusions: Atazanavir is a potent, safe, well tolerated, and effective once-daily protease inhibitor with low pill burden (two capsules/day). Lipid changes with atazanavir were significantly less than with nelfinavir, however, clinical significance of these finding in terms of decreased cardiovascular risk is unknown.

CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial.

BACKGROUND Stopping antiretroviral therapy in patients with HIV-1 infection can reduce costs and side-effects, but carries the risk of increased immune suppression and emergence of resistance. METHODS 430 patients with CD4-positive T-lymphocyte (CD4) counts greater than 350 cells per muL, and viral load less than 50 copies per mL were randomised to continued therapy (n=146) or scheduled treatment interruptions (n=284). Median time on randomised treatment was 21.9 months (range 16.4-25.3). Primary endpoints were proportion of patients with viral load less than 50 copies per mL at the end of the trial, and amount of drugs used. Analysis was intention-to-treat. This study is registered at ClinicalTrials.gov with the identifier NCT00113126. FINDINGS Drug savings in the scheduled treatment interruption group, compared with continuous treatment, amounted to 61.5%. 257 of 284 (90.5%) patients in the scheduled treatment interruption group reached a viral load less than 50 copies per mL, compared with 134 of 146 (91.8%) in the continued treatment group (difference 1.3%, 95% CI-4.3 to 6.9, p=0.90). No AIDS-defining events occurred. Diarrhoea and neuropathy were more frequent with continuous treatment; candidiasis was more frequent with scheduled treatment interruption. Ten patients (2.3%) had resistance mutations, with no significant differences between groups. INTERPRETATION Drug savings with scheduled treatment interruption were substantial, and no evidence of increased treatment resistance emerged. Treatment-related adverse events were more frequent with continuous treatment, but low CD4 counts and minor manifestations of HIV infection were more frequent with scheduled treatment interruption.

An Algorithm for Tuberculosis Screening and Diagnosis in People with HIV

BACKGROUND Tuberculosis screening is recommended for people with human immunodeficiency virus (HIV) infection to facilitate early diagnosis and safe initiation of antiretroviral therapy and isoniazid preventive therapy. No internationally accepted, evidence-based guideline addresses the optimal means of conducting such screening, although screening for chronic cough is common. METHODS We consecutively enrolled people with HIV infection from eight outpatient clinics in Cambodia, Thailand, and Vietnam. For each patient, three samples of sputum and one each of urine, stool, blood, and lymph-node aspirate (for patients with lymphadenopathy) were obtained for mycobacterial culture. We compared the characteristics of patients who received a diagnosis of tuberculosis (on the basis of having one or more specimens that were culture-positive) with those of patients who did not have tuberculosis to derive an algorithm for screening and diagnosis. RESULTS Tuberculosis was diagnosed in 267 (15%) of 1748 patients (median CD4+ T-lymphocyte count, 242 per cubic millimeter; interquartile range, 82 to 396). The presence of a cough for 2 or 3 weeks or more during the preceding 4 weeks had a sensitivity of 22 to 33% for detecting tuberculosis. The presence of cough of any duration, fever of any duration, or night sweats lasting 3 or more weeks in the preceding 4 weeks was 93% sensitive and 36% specific for tuberculosis. In the 1199 patients with any of these symptoms, a combination of two negative sputum smears, a normal chest radiograph, and a CD4+ cell count of 350 or more per cubic millimeter helped to rule out a diagnosis of tuberculosis, whereas a positive diagnosis could be made only for the 113 patients (9%) with one or more positive sputum smears; mycobacterial culture was required for most other patients. CONCLUSIONS In persons with HIV infection, screening for tuberculosis should include asking questions about a combination of symptoms rather than only about chronic cough. It is likely that antiretroviral therapy and isoniazid preventive therapy can be started safely in people whose screening for all three symptoms is negative, whereas diagnosis in most others will require mycobacterial culture.

Impact of Multi-Targeted Antiretroviral Treatment on Gut T Cell Depletion and HIV Reservoir Seeding during Acute HIV Infection

Background Limited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy. Methods and Findings We prospectively screened 24,430 subjects in Bangkok and identified 40 AHI individuals. Thirty Thais were enrolled (8 Fiebig I, 5 Fiebig II, 15 Fiebig III, 2 Fiebig IV) of whom 15 completed 24 weeks of megaHAART (tenofovir/emtricitabine/efavirenz/raltegravir/maraviroc). Sigmoid biopsies were completed in 24/30 at baseline and 13/15 at week 24. At baseline, the median age was 29 years and 83% were MSM. Most were symptomatic (87%), and were infected with R5-tropic (77%) CRF01_AE (70%). Median CD4 was 406 cells/mm3. HIV RNA was 5.5 log10 copies/ml. Median total blood HIV DNA was higher in Fiebig III (550 copy/106 PBMC) vs. Fiebig I (8 copy/106 PBMC) (p = 0.01) while the median %CD4+CCR5+ gut T cells was lower in Fiebig III (19%) vs. Fiebig I (59%) (p = 0.0008). After 24 weeks of megaHAART, HIV RNA levels of <50 copies were achieved in 14/15 in blood and 13/13 in gut. Total blood HIV DNA at week 0 predicted reservoir size at week 24 (p<0.001). Total HIV DNA declined significantly and was undetectable in 3 of 15 in blood and 3 of 7 in gut. Frequency of CD4+CCR5+ gut T cells increased from 41% at baseline to 64% at week 24 (p>0.050); subjects with less than 40% at baseline had a significant increase in CD4+CCR5+ T cells from baseline to week 24 (14% vs. 71%, p = 0.02). Conclusions Gut T cell depletion and HIV reservoir seeding increases with progression of AHI. MegaHAART was associated with immune restoration and reduced reservoir size. Our findings could inform research on strategies to achieve HIV drug-free remission.

Myelin Basic Protein as an Encephalitogen in Encephalomyelitis and Polyneuritis Following Rabies Vaccination

Encephalitis and polyneuritis occurring after rabies vaccination are believed to be immunologically mediated. We studied antibody responses to neural antigens in 36 patients with major neurologic complications, 25 with minor complications, and 39 with no complications after immunization with a brain-derived, Semple rabies vaccine. Patients with major complications had significantly elevated levels of antibody to brain white matter as compared with the other groups (P less than 0.001). Assays for antibody to selected central nervous system antigens showed that high levels of serum and cerebrospinal fluid antibody to myelin basic protein correlated with the presence of major neurologic complications (both central and peripheral nervous systems). The level of antibody to cerebroside correlated best with the number of injections of vaccine, but like antibody to myelin basic protein, the antibody to cerebroside was present in the cerebrospinal fluid of patients with major complications. Some patients with major complications also had antibodies directed to the gangliosides GD1b and GT1b. No antibodies to myelin-associated glycoprotein were detected in any of the samples. These data implicate myelin basic protein as an encephalitogen in these autoimmune diseases of the human nervous system, but suggest that immune responses to cerebroside and certain gangliosides may have an augmentative role in severe disease.

Evidence of a previously undocumented epidemic of HIV infection among men who have sex with men in Bangkok, Thailand

Background:The HIV prevalence and associated risk behaviours in Thai men who have sex with men (MSM) are unknown. This information is crucial to inform and implement targeted preventive interventions for this population. Methods:A cross-sectional assessment, using venue–day–time sampling, was conducted. Participants were 1121 Thai men who were 18 years or older, were residents of Bangkok, and reported anal or oral sex with a man during the past 6 months. Oral fluid specimens were tested for HIV antibody. Demographic and behavioural data were collected using an interviewer-administered Palm based automated questionnaire. Results:HIV prevalence was 17.3% (194 of 1121). Mean age was 26.9 years (median 25 years), and university education was completed by 42.5%. Sex with men and women during the past 6 months was reported by 22.3%; sex with a woman ever, 36%; and unprotected sexual intercourse during the past 3 months, 36.0%. Alcohol use during the past 3 months was common (73.7%); drug use was rare (2.5%). Multivariate logistic regression analyses showed lower education, recruitment from a park, self-identification as homosexual, receptive and insertive anal intercourse, more years since first anal intercourse, and more male sex partners to be significantly and independently associated with HIV prevalence. Conclusions:HIV infection is common among MSM in Bangkok. HIV prevention programs are urgently needed to prevent further spread of HIV in this young and sexually active population.

Impact of viral hepatitis co-infection on response to antiretroviral therapy and HIV disease progression in the HIV-NAT cohort.

Objective: To examine the impact of viral hepatitis co-infection on HIV disease outcomes following commencement of combination antiretroviral therapy in a developing country setting. Methods: HIV RNA suppression, CD4 cell count recovery, and HIV disease progression were examined within a cohort of Thai HIV-infected patients enrolled in eight HIV-NAT randomized controlled trials of antiretroviral therapy (n = 692). Hepatitis B virus (HBV) and hepatitis C virus (HCV) testing was performed on stored serum. Results: Mean age was 32.3 years, 52% were male, 11% had CDC category C HIV disease at baseline, and 22% had received prior antiretroviral therapy. Prevalence of HBV, HCV and HBV/HCV co-infection was 8.7, 7.2 and 0.4%, respectively. Median HIV RNA reductions (log10 copies/ml) were approximately 1.5 for HIV, HIV-HBV, HIV-HCV subgroups from week 4 up to week 48. Mean increases in CD4 cell count were significantly lower among HIV-HBV and HIV-HCV subgroups at week 4 (HIV, 62 × 106 cells/l; HIV-HBV, 29 × 106 cells/l; HIV-HCV, 33 × 106 cells/l), however, by week 48 CD4 cell increases were similar (HIV, 115 × 106 cells/l; HIV-HBV, 113 × 106 cells/l; HIV-HCV, 97 × 106 cells/l). Cox regression analyses showed that HIV-HBV or HIV-HCV co-infection were not associated with a CD4 cell count increase of 100 × 106 cells/l over 48 weeks. Estimated progression to AIDS event or death at week 48 was 3.3% (95% confidence interval, 2.0–5.1%) for HIV, 6.7% (2.5–14.6%) for HIV-HBV, and 8.0% (2.2–20.5%) for HIV-HCV subgroups (P > 0.05). Conclusions: An early delayed CD4 count recovery among HIV/viral hepatitis co-infected patients was not sustained, and was not associated with increased HIV disease progression.

Trends in HIV Prevalence, Estimated HIV Incidence, and Risk Behavior Among Men Who Have Sex With Men in Bangkok, Thailand, 2003–2007.

Background:Men who have sex with men (MSM) continue to be at high risk for HIV infection. Here we evaluate trends in HIV prevalence, estimated HIV incidence, and risk behavior among MSM in Bangkok, Thailand. Methods:Between 2003 and 2007, 3 biennial cross-sectional HIV prevalence assessments were conducted among MSM in Bangkok, Thailand, using venue-day-time sampling. Oral fluid was tested for HIV infection; demographic and behavioral data were self-collected using hand-held computers. Estimates of annual HIV incidence in young MSM were derived as follows: (number of HIV infections/sum of [current age-age at start of anal intercourse]) × 100). Logistic and Poisson regression was used to evaluate trends in HIV prevalence, estimated HIV incidence, and risk behavior. Findings:The overall HIV prevalence increased from 17.3% in 2003 to 28.3% in 2005 to 30.8% in 2007 (P < 0.001 for trend). The estimated HIV incidence among young MSM increased from 4.1% in 2003 to 6.4% in 2005, to 7.7% in 2007 (P < 0.02 for trend). The increase in HIV prevalence from 2005 to 2007 was not statistically significant. The proportion of men reporting anal sex and casual or steady male sex partners in the past 3 months significantly decreased, whereas the proportion reporting drug use and drug use during sex significantly increased. No increase was observed in the proportion of men reporting consistent condom use. Interpretation:Our data suggest that after a strong increase from 2003 to 2005, the HIV prevalence among MSM in Bangkok may have begun to stabilize. Given the continuing high levels of risk behavior and the estimated high HIV incidence in young MSM, additional HIV preventive interventions are necessary.