Warangkana Munsakul

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.

A randomized comparison of second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI regimens: the HIV STAR study.

BACKGROUND Data informing the use of boosted protease inhibitor (PI) monotherapy as second-line treatment are limited. There are also no randomized trials addressing treatment options after failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-regimens. METHODS HIV-infected subjects ≥18 years, with HIV RNA≥1,000 copies/ml while using NNRTI plus 2 NRTIs, and naive to PIs were randomized to lopinavir/ritonavir (LPV/r) 400/100 mg twice daily monotherapy (mono-LPV/r) or tenofovir disoproxil fumarate (TDF) once daily plus lamivudine (3TC) twice daily plus LPV/r 400/100 mg twice daily (TDF/3TC/LPV/r) at nine sites in Thailand. The primary outcome was time-weighted area under curve (TWAUC) change in HIV RNA over 48 weeks. The a priori hypothesis was that the mono-LPV/r arm would be considered non-inferior if the upper 95% confidence limit in TWAUC mean difference was ≤0.5 log(10) copies/ml. RESULTS The intention-to-treat (ITT) population comprised 195 patients (mono-LPV/r n=98 and TDF/3TC/LPV/r n=97): male 58%, baseline mean (sd) age of 38 (7) years, CD4(+) T-cell count of 204 (135) cells/mm(3) and HIV RNA of 4.1 (0.6) log(10) copies/ml. The majority had HIV-1 recombinant CRF01_AE infection, and thymidine analogue mutation (TAM)-2 was 3× more common than TAM-1. At 48 weeks, the difference in TWAUC HIV RNA between arms was 0.15 (95% CI -0.04, 0.33) log(10) copies/ml, consistent with our definition of non-inferiority. However, the proportion with HIV RNA<50 copies/ml was significantly lower in the mono-LPV/r arm: 61% versus 83% (ITT, P<0.01). Baseline HIV RNA≥5 log(10) copies/ml (P<0.001) and mono-LPV/r use (P=0.003) were predictors of virological failure. Baseline genotypic sensitivity scores ≥2 and TAM-2 were associated with better virological control in subjects treated with the TDF-containing regimen. CONCLUSIONS In PI-naive patients failing NNRTI-based first-line HAART, mono-LPV/r had a significantly lower proportion of patients with HIV RNA<50 copies/ml compared to the TDF/3TC/LPV/r treatment. Thus, mono-LPV/r should not be recommended as a second-line option.

Etravirine and rilpivirine resistance in HIV-1 subtype CRF01_AE-infected adults failing non-nucleoside reverse transcriptase inhibitor-based regimens.

BACKGROUND We studied prevalence of etravirine (ETR) and rilpivirine (RPV) resistance in HIV-1 subtype CRF01_AE infection with first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) failure. METHODS A total of 225 adults failing two nucleoside reverse transcriptase inhibitors (NRTIs) plus 1 NNRTI in Thailand with HIV RNA>1,000 copies/ml were included. Genotypic resistance results and HIV-1 subtype were interpreted by Stanford DR database. ETR resistance was calculated by the new Monogram weighted score (Monogram WS; ≥ 4 indicating high-level ETR resistance) and by DUET weighted score (DUET WS; 2.5-3.5 and ≥ 4 resulted in intermediate and reduce ETR response, respectively). RPV resistance interpretation was based on previous reports. RESULTS Median (IQR) age was 38 (34-42) years, 41% were female and CDC A:B:C were 22%:21%:57%. HIV subtypes were 96% CRF01_AE and 4% B. Antiretrovirals at failure were lamivudine (100%), stavudine (93%), nevirapine (90%) and efavirenz (10%) with a median (IQR) duration of 3.4 (1.8-4.5) years. Median (IQR) CD4(+) T-cell count and HIV RNA were 194 (121-280) cells/mm³ and 4.1 (3.6-4.6) log₁₀ copies/ml, respectively. The common NNRTI mutations were Y181C (41%), G190A (22%) and K103N (19%). The proportion of patients with Monogram WS score ≥ 4 was 61.3%. By DUET WS, 49.8% and 7.5% of patients were scored 2.5-3.5 and ≥4, respectively. Only HIV RNA ≥ 4 log₁₀ copies/ml at failure was associated with both Monogram WS ≥ 4 (OR 2.3, 95% CI 1.3-3.9; P=0.003) and DUET WS ≥ 2.5 (OR 1.9, 95% CI 1.1-3.3; P=0.02). The RVP resistance-associated mutations (RAMs) detected were K101P (1.8%), Y181I (2.7%) and Y181V (3.6%). All patients with RPV mutation had ETR resistance. No E138R/E138K mutations were detected. CONCLUSIONS Approximately 60% of patients had high-level ETR resistance. The role of ETR in second-line therapy is limited in late NNRTI failure settings. RVP RAMs were uncommon, but cross-resistance between ETR and RVP was high.

The impact of combination antiretroviral therapy and its interruption on anxiety, stress, depression and quality of life in Thai patients

Objective: Investigation on anxiety, stress, depression, and quality of life (QoL) within STACCATO, a randomised trial of two treatment strategies: CD4 guided scheduled treatment interruption (STI) compared to continuous treatment (CT). Participants: Thai patients with HIV-infection enrolled in the STACCATO trial. Methods: Anxiety, depression assessed by the questionnaires Hospital Anxiety and Depression Scale (HADS) and DASS, stress assessed by the Depression Anxiety Stress Scale (DASS), and QoL evaluated by the HIV Medical Outcome Study (MOS-HIV) questionnaires. Answers to questionnaires were evaluated at 4 time-points: baseline, 24 weeks, 48 weeks and at the end of STACCATO. Results: A total of 251 patients answered the HADS/DASS and 241 answered the MOS-HIV of the 379 Thai patients enrolled into STACCATO (66.2 and 63.6% respectively). At baseline 16.3% and 7.2% of patients reported anxiety and depression using HADS scale. Using the DASS scale, 35.1% reported mild to moderate and 9.6% reported severe anxiety; 8.8% reported mild to moderate and 2.0% reported severe depression; 42.6% reported mild to moderate and 4.8% reported severe stress. We showed a significant improvement of the MHS across time (p=0.001), but no difference between arms (p=0.17). The summarized physical health status score (PHS) did not change during the trial (p=0.15) nor between arm (p=0.45). There was no change of MHS or PHS in the STI arm, taking into account the number of STI cycle (p=0.30 and 0.57) but MHS significant increased across time-points (p=0.007). Conclusion: Antiretroviral therapy improved mental health and QOL, irrespective of the treatment strategy.

Low-dose versus standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai adults with HIV (LASA): a randomised, open-label, non-inferiority trial

BACKGROUND Thai patients with HIV have higher exposure to HIV protease inhibitors than do white people and dose reduction might be possible. We compared the efficacy of low-dose with standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai patients with HIV. METHODS In this randomised, open-label, non-inferiority trial, we recruited patients aged 18 years or older who were receiving ritonavir-boosted protease-inhibitor-based antiretroviral therapy (ART) with HIV plasma viral loads of less than 50 copies per mL, an alanine aminotransferase concentration of less than 200 IU/L, and a creatinine clearance of at least 60 mL/min from 14 hospitals in Thailand. We excluded patients who had active AIDS-defining disease or opportunistic infections, had a history of an HIV viral load of 1000 copies per mL or more after 24 weeks of any ritonavir-boosted protease-inhibitor-based ART, used concomitant medications that could interact with the study drugs, were pregnant or lactating, had illnesses that might change the effect of the study drugs, or had a history of sensitivity to the study drugs. A biostatistician at the study coordinating centre randomly allocated patients (1:1) to switch the protease inhibitor for oral atazanavir 200 mg and ritonavir 100 mg or for atazanavir 300 mg and ritonavir 100 mg once daily, both with two nucleoside or nucleotide reverse transcriptase inhibitors at recommended doses. Randomisation was done with a minimisation schedule, stratified by recruiting centre, use of tenofovir, and use of indinavir as a component of the preswitch regimen. The primary endpoint was the proportion of patients with viral loads of less than 200 copies per mL at week 48, and we followed up patients every 12 weeks. Treatments were open label, the non-inferiority margin was -10%, and all patients who received at least one dose of study medication were analysed. This trial is registered with ClinicalTrials.gov, number NCT01159223. FINDINGS Between July 6, 2011, and Dec 23, 2013, we randomly assigned 559 patients: 279 to receive atazanavir 200 mg and ritonavir 100 mg (low dose) and 280 to atazanavir 300 mg and ritonavir 100 mg (standard dose). At week 48, 265 (97·1%) of 273 in the low-dose group and 267 (96·4%) of 277 in the standard-dose group had viral loads of less than 200 copies per mL (difference 0·68; 95% CI -2·29 to 3·65). Seven (3%) of 273 in the low-dose group and 21 (8%) of 277 in the standard-dose group discontinued their assigned treatment (p=0·01). 46 (17%) of 273 participants in the low-dose group and 97 (35%) of 277 in the standard-dose group had total bilirubin grade 3 or higher toxicity (≥3·12 mg/dL; p<0·0001). INTERPRETATION A switch to low-dose atazanavir should be recommended for Thai patients with well controlled HIV viraemia while on regimens based on boosted protease inhibitors. FUNDING The National Health Security Office and Kirby Institute for Infection and Immunity in Society.

HIV-1 genital shedding in HIV-infected patients randomized to second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir.

BACKGROUND HIV-1 shedding in genital secretions is associated with HIV transmission risk. Limited data exist on the effect of second-line lopinavir/ritonavir monotherapy (mLPV/r) on genital secretion of HIV RNA. METHODS We measured HIV-1 in genital secretions of HIV-infected adults at time of failure from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and at 48 weeks after being randomized to second-line mLPV/r versus tenofovir/lamivudine/LPV/r (TDF/3TC/LPV/r). Plasma and genital secretion (semen, vaginal swab) HIV RNA was quantified by the CobasAmpliprep/TaqMan assay. RESULTS Forty enrolled (15 on mLPV/r and 25 on TDF/3TC/LPV/r). Median age was 37.8 years and 35% were male. Median baseline CD4(+) T-cell count was 222 cells/mm(3), plasma HIV RNA was 4.1 log10 copies/ml and genital secretion HIV RNA was 2.3 log10 copies/ml. At week 48, the proportion of patients with plasma HIV RNA<50 copies/ml was 13/15 (87%) in mLPV/r and 21/25 (84%) in TDF/3TC/LPV/r arms. Median genital HIV RNA was significantly decreased from baseline in both arms (P=0.009 in mLPV/r and P=0.001 in TDF/3TC/LPV/r). In subjects with suppressed plasma HIV RNA, 12/34 (35%; 6/13 [46%] in the mLPV/r and 6/21 [29%] in the TDF/3TC/LPV/r arms) had detectable HIV RNA (range 74-957 copies/ml) in the genital secretions (P=0.41). By multivariate analysis, the only predictor of having genital HIV RNA>50 copies/ml at week 48 was baseline genital secretion HIV RNA>50 copies/ml (P=0.049). CONCLUSIONS LPV/r either given alone or in combination with TDF/3TC as second-line treatment achieved high genital secretion HIV RNA suppression rate. Genital secretion HIV RNA remained detectable at low levels in one-third of patients with suppressed plasma viraemia.

Supersensitive Viral Load Assay in Predicting CD4-Guided Treatment Failure

In HIV patients who discontinue highly active antiretroviral therapy (HAART), the degree of HIV RNA suppression at the time of treatment interruption may predict success of re-treatment after the interruption (STI). A case-control substudy of the Staccato trial in Thailand included CD4-guided STI subjects with HIV RNA > 50 copies /ml (virological failure cases, n=11) and HIV RNA < 50 copies/ml (controls, n=22) after 12-24 weeks of HAART re-treatment following a median of 2 STI cycles. Controls were matched for age, gender and pre-ART CD4 count. HIV RNA with 5 copies/ml detection limit was determined on pre-virological failure samples. HIV RNA increased in cases compared to controls with each successive STI cycle (p-trend across time-points 0.004). The last HIV RNA below 50 copies/ml was significantly higher among cases compared to controls (p=.004). Measuring HIV RNA below 50 copies/ml may be useful in predicting virological failure to STI.

Implementation and assessment of a prevention with positives intervention among people living with HIV at five hospitals in Thailand

Background We implemented a hospital-based prevention with positives (PwP) intervention among people living with HIV (PLHIV) that included HIV transmission risk screening, short HIV prevention messages, family planning, HIV disclosure counseling, and partner HIV testing at five hospitals in Thailand. We assessed changes in sexual risk behaviors among PLHIV who received the PwP services at the hospitals. Methods From January 2008-March 2009, we systematically selected a subset of PLHIV receiving care at the five hospitals to offer participation in the PwP intervention. We collected demographic, risk behavior, and laboratory data using a standardized questionnaire. We analyzed data from PLHIV who completed at least four visits, using generalized estimating equations to identify baseline participant characteristics that were associated with adopting sexual practices less likely to be associated with HIV transmission during follow-up. Results A total of 830 PLHIV were interviewed and 756 (91.1%) completed four visits. The median age of these 756 participants was 37 years, 400 (52.9%) were women, and 475 (62.8%) had a steady partner. At baseline, 353 (74.3%) of the steady partners had been tested for HIV and 132 (37.4%) had tested negative. Among the 756 PLHIV, 427 (56.5%) reported having sex in the 3 months before enrollment and 413 (54.6%) in the 3 months before the fourth visit. The proportion reporting having vaginal or anal sex without a condom decreased from 20.8% at baseline to 5.1% at the fourth visit (p<0.001). Factors associated (p<0.05) with abstinence or 100% condom use at follow-up visits included: completing ≥ two visits, being diagnosed with HIV for longer than 3 months, and receiving HIV prevention messages from a doctor (versus a nurse or counselor). Conclusion Safe sex behaviors increased among PLHIV receiving PwP services, suggesting that expansion of hospital-based PwP services may reduce the number of new HIV infections in Thailand.