Dual Nucleoside Reverse Transcriptase Inhibitor Research Articles

Use of integrase inhibitors vs protease inhibitors is associated with improved HIV viral suppression

Current guidelines for antiretroviral therapy in pregnancy include the use of a dual-nucleoside reverse transcriptase inhibitor with either an integrase strand transfer inhibitor or a ritonavir-boosted protease inhibitor, although there is no designation of which is the preferred option. This study aimed to compare viral suppression at delivery among patients on dual-nucleoside reverse transcriptase inhibitors combined with either an integrase strand transfer inhibitor or a protease inhibitor. A hypothesis was made that the incidence of viral suppression is higher with the use of a dual-nucleoside reverse transcriptase inhibitor backbone combined with an integrase strand transfer inhibitor than with the use of a dual-nucleoside reverse transcriptase inhibitor backbone combined with a protease inhibitor. This study was an observational study of pregnant patients living with HIV who received prenatal care and delivered after 20 weeks of gestation at an urban safety net hospital. All pregnant patients with HIV were referred to a centralized clinic for HIV counseling, medication management, and prenatal care. Antiretroviral therapy was continued or initiated according to protocols based on national guidance. Among patients on a dual-nucleoside reverse transcriptase inhibitor backbone combined with integrase strand transfer inhibitor vs protease inhibitor at delivery, we compared the demographics and HIV disease characteristics, including year of diagnosis, viral load, and antiretroviral therapy class. The outcome of interest was viral suppression at delivery, defined as a viral load of <50 copies/mL. From January 2011 to December 2021, 604 patients on dual-nucleoside reverse transcriptase inhibitor met the inclusion criteria, including 411 patients (68%) on protease inhibitor and 193 patients (32%) on integrase strand transfer inhibitor at delivery. Demographic distribution was similar, and prenatal care was initiated at 12 weeks of gestation. Among the integrase strand transfer inhibitor group, 101 (17%) were on antiretroviral therapy at initiation of prenatal care compared with 169 (28%) in the protease inhibitor group. At delivery, the frequency of viral load suppression was higher among those on an integrase strand transfer inhibitor (147/193 [76%]) than among those on a protease inhibitor (275/411 [67%]) (odds ratio, 1.59; 95% confidence interval, 1.08-2.33). Among those with a detectable virus, quantitative viral load was not different. During the study period, the use of a protease inhibitor decreased, whereas the use of an integrase strand transfer inhibitor increased. Among pregnant patients living with HIV, viral suppression was more common among those on a dual-nucleoside reverse transcriptase inhibitor backbone combined with integrase strand transfer inhibitor than among those on a dual-nucleoside reverse transcriptase inhibitor backbone protease inhibitor at delivery. Our results support the use of dual-nucleoside reverse transcriptase inhibitor with integrase strand transfer inhibitor as a first-line antiretroviral therapy regimen in pregnancy.

Revisiting efavirenz in the era of dolutegravir: Low-dose efavirenz, a viable alternative capable of holding its own against dolutegravir-based regimens

ABSTRACT Background: First-line dual NRTI + NNRTI-based ART has shown good virological effectiveness; however, toxicity is common and is often the most common reason for modification of first-line ART. Aims: The purpose of this study is to revisit low-dose efavirenz (EFV) in the era of dolutegravir (DTG) by investigating anti-retroviral therapy (ART) switch strategies for outcomes of virological effectiveness and safety in virologically suppressed Indian persons living with HIV (PLH) on first-line dual nucleoside reverse transcriptase inhibitors (NRTI) + non-NRTI (NNRTI)-based ART. Methods: A phase-IV comparative study of consecutive cases who switched their first-line NNRTI-based ART to either EFV-400 or DTG with a dual NRTI backbone between October 2020 to December 2021 and underwent at least 48 weeks of follow-up. The study is a non-randomised trial, wherein ART regimens were based on physician choice, patient preference and drug availability. Results: A total of 102 [DTG arm: 52; EFV-400 arm: 50; intention-to-treat (ITT) population] participants met the inclusion criteria. At 48-week follow-up, virological failure was not observed in either arm. Virological suppression to &lt; 200 cp/mL was attained in 97.9% (n = 48/49; 95% confidence interval [CI]: 89.1–99.9) and 95.9% (n = 47/49; 95% CI: 86.02–99.5) of patients, respectively, in the DTG and-EFV-400 arm (ITT-populations). There was no significant difference in mean change from baseline in body weight and body mass index between DTG and-EFV-400 arms. The proportion of patients who gained ≥ 10% of their baseline body weight at 24 weeks of exposure to DTG was 16% (n = 8, 95% CI: 5.8 to 26.2) and that to EFV-400 was 10% (n = 5, 95% CI: 1.7 to 18.3) with a difference in proportions: 6.0% (95% CI: −7.1–19.1)]. There was a significant decrease at 24 weeks in mean fasting levels of lipid fractions in the DTG arm as compared to EFV-400 [total cholesterol: − 24.3 mg/dL, 95% CI: −35.2 to − 13.3 vs. −6.9 mg/dL, 95% CI: −17.9–4.1 (P = 0.029) and triglycerides:−35.9 mg/dL, 95% CI: −60.9 to − 10.9 vs. 8.6 mg/dL, 95% CI: −16.6 to 33.8 (P = 0.014)]. Adverse events (AEs) of any grade including laboratory derangements to DTG were experienced by 6% (n = 3, 95% CI: −0.6 to 12.6) and that to EFV-400 by 8% (n = 4, 95% CI: 0.5 to 15.5) with a difference in proportions: 2.0% (95% CI: −7.9 to 11.9). Grades 3–4-AE occurred in two patients, both in the EFV-400 arm. Central nervous system AEs were not observed in the DTG arm and occurred in two patients in the EFV-400 arm. Two patients in the EFV-400 arm discontinued the regimen due to AEs. Conclusion: Both DTG and EFV-400-based first-line ART show good virological effectiveness and safety profiles in patients who are virologically suppressed on dual NRTI + NNRTI-based first-line ART.

Antiretroviral Options and Treatment Decisions During Pregnancy.

The majority of pediatric human immunodeficiency virus (HIV) infections are the result of vertical transmissions that occur during pregnancy, childbirth, and breastfeeding. The treatment of all pregnant persons living with HIV remains a global health initiative. Early and consistent use of antiretroviral therapy throughout pregnancy and childbirth drastically reduces the risk of perinatal transmission of HIV, resulting in fewer children living with the disease worldwide. Given that the maternal HIV viral load is the strongest predictor of perinatal transmission, suppressive antiretroviral treatment during pregnancy is the principal means to eliminate transmission of HIV from mother to child. With the use of combined antiretroviral therapy, typically with dual-nucleoside reverse transcriptase inhibitors plus an integrase strand transfer inhibitor or a ritonavir-boosted protease inhibitor, HIV-infected mothers can now achieve virologic suppression to undetectable levels and yield a perinatal transmission rate of less than 2%. Important considerations of HIV treatment in pregnancy include the safety and efficacy of antiretroviral drugs, altered pregnancy-related pharmacokinetics, potential for birth defects or adverse neonatal outcomes, and individualized delivery planning based on maternal viral load. This practical review article summarizes the options, considerations, and recommendations for antiretroviral treatment in pregnancy to reduce perinatal HIV transmission and optimize health outcomes for mothers and infants worldwide.

Is Antiretroviral Two-Drug Regimen the New Standard for HIV Treatment in Naive Patients?

The use of a combination antiretroviral therapy (cART) has changed dramatically the prognosis and the life expectancy of people living with HIV. The current treatment guidelines continue the convention of preferred cART based on combining a dual nucleoside reverse-transcriptase inhibitor (NRTI) backbone with a third "anchor" agent, such as a ritonavir (r)- or cobicistat (c)-boosted protease inhibitor (PI), a non-NRTI (NNRTI), or an integrase inhibitor (INI) boosted or unboosted. However, due to toxicities of NRTIs, sparing NRTI regimen has been studied for a long time with moderate success due to low efficacy (especially in patients with high viral load and low CD4) compare to standard triple therapy. New strategy with lamivudine (3TC) plus a boosted PI or INI showed promise results and indicated that modern two-drug regimens might now, in fact, become a reliable treatment for HIV-infected naïve patients. This article discusses recent data from dual therapy studies in naïve HIV-infected patients and the challenges behind this strategy.

Impact of antiretroviral treatment on height evolution of HIV infected children

BackgroundAntiretroviral treatment (ART) has been shown to have a beneficial effect on the weight evolution but its effect on height remains unclear. We described patterns of height evolution and identified predictors of catch-up growth in HIV-infected children on ART.MethodsTo describe the height evolution from birth to adulthood, we developed a nonlinear mixed effect model using data from perinatally HIV-infected children who initiated ART from 1999 to 2013 in a prospective cohort study in Thailand. The main covariates of interest were: sex, ART regimen (dual nucleoside reverse-transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or protease inhibitor (PI)-based), baseline CD4 percentage, HIV-RNA load and CDC HIV Classification stage and occurrence of AIDS-defining events.ResultsA total 477 children (43% boys) contributed 18,596 height measurements over a median duration of 6.3 years on ART (interquartile range, 3.0 to 8.3). At ART initiation, median age was 6.2 years (1.8 to 9.6), 16% of children were underweight (weight-for-age z-score < − 2), 49% presented stunting (height-for-age z-score < − 2), and 7% wasting (weight-for-height z-score < − 2). The most frequent regimen at ART initiation was NNRTI-based (79%). A model with 4 components, birth length and 3 exponential functions of age accounting for the 3 growth phases was developed and show that the height-growth velocity was inversely associated with the age at ART initiation, the adult height was significantly lower in those who had experienced at least one AIDS-defining event while, as expected, the model found that adult height in females was lower than in males. Age at ART initiation, type of ART regimen, CDC stage, CD4 percentages, and HIV-RNA load were not associated with the final height.ConclusionsThe younger the children at ART initiation, the greater the effect on height-growth velocity, supporting the World Health Organization’s recommendation to start ART as early as possible. However, final adult height was not linked to the age at ART initiation.

Dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with HIV-1 infection in whom first-line therapy has failed (DAWNING): an open-label, non-inferiority, phase 3b trial

Doubts exist regarding optimal second-line treatment options for HIV-1-infected patients in resource-limited settings. We assessed safety and efficacy of dolutegravir compared with ritonavir-boosted lopinavir, plus two nucleoside reverse transcriptase inhibitors (NRTIs) in adults in whom previous first-line antiretroviral therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two NRTIs has failed. DAWNING is a phase 3b, open-label, parallel-group, non-inferiority, active-controlled trial done at 58 sites in 13 countries. Eligible adults were aged at least 18 years and, during at least 6 months of treatment with a first-line treatment containing an NNRTI and two NRTIs, had virological failure (confirmed HIV-1 RNA ≥400 copies per mL). Participants were randomly assigned by a central randomisation system to receive oral dolutegravir (50 mg once daily) or ritonavir-boosted lopinavir (800 mg lopinavir plus 200 mg ritonavir once daily or 400 mg plus 100 mg twice daily), plus two investigator-selected NRTIs (at least one fully active based on resistance testing at screening). The primary outcome was the proportion of participants achieving viral suppression (defined as plasma HIV-1 RNA <50 copies per mL) at week 48 using the snapshot algorithm and a non-inferiority margin of -12%. The primary analysis was done in an intention-to-treat-exposed (ITT-E) population of participants who received at least one dose of study medication, according to original group assignment. Safety was analysed in all participants who received at least one dose of study drug, according to which drug was received. The study was registered at ClinicalTrials.gov, number NCT02227238, and viiv-studyregister.com, number 200304. Between Dec 11, 2014, and June 27, 2016, 968 adults were screened and 627 were randomly assigned to the dolutegravir group (n=312) or the ritonavir-boosted lopinavir group (n=315). Three patients in the ritonavir-boosted lopinavir group did not receive study medication and so 624 were included in the ITT-E population. At week 48, 261 (84%) of 312 participants in the dolutegravir group achieved viral suppression compared with 219 (70%) of 312 in the ritonavir-boosted lopinavir group (adjusted difference 13·8%; 95% CI 7·3-20·3). Non-inferiority was achieved on the basis of the 95% CI of the adjusted treatment difference having a lower bound greater than -12% (prespecified non-inferiority margin). Because the lower bound of the 95% CI is greater than zero (7·3%), superiority of dolutegravir was also concluded (p<0·0001). The safety profile for dolutegravir was favourable compared with that of ritonavir-boosted lopinavir. More grade 2-4 drug-related adverse events occurred with ritonavir-boosted lopinavir than dolutegravir (44 [14%] of 310 with ritonavir-boosted lopinavir vs 11 [4%] of 314 with dolutegravir), mainly driven by gastrointestinal disorders. When administered with two NRTIs, dolutegravir was superior to ritonavir-boosted lopinavir at 48 weeks and can be considered a suitable option for second-line treatment. ViiV Healthcare.

Single-tablet antiretroviral treatment (once daily).

Current guidelines recommend combination antiretroviral treatment for all patients with HIV infection.[1][1],[2][2] The backbone of this treatment regimen is a dual nucleoside reverse transcriptase inhibitor combination, typically tenofovir/emtricitabine or abacavir/lamivudine, which is combined

Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial

In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals. In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01641809. Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 [87%] of 60, 51 [85%] of 60, and 53 [87%] of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24, 149 (82%; 95% CI 77-88) patients in the cabotegravir groups (48 [80%; 70-90], 48 [80%; 70-90], and 53 [87%; 78-95] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60-82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69-82) receiving cabotegravir (41 [68%; 57-80], 45 [75%; 64-86], and 51 [84%; 74-93] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51-75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 [47%], 32 [53%], and 33 [54%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one [2%], one [2%], and four [7%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group. Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection. ViiV Healthcare and Janssen Research and Development.

The long-term outcomes of antiretroviral treatment initiated with mono or dual nucleoside reverse transcriptase inhibitors in HIV-1-infected children: an Asian observational study

After a median of 115.9 months of follow-up, 90% of 206 HIV-1-infected children in a cohort in Asia who initiated antiretroviral treatment (ART) with mono or dual nucleoside reverse transcriptase inhibitors were alive and had comparable immunological and virological outcomes as compared to the 1,915 children who had started with highly active antiretroviral regimens. However, these children had higher rates of treatment-related adverse events, opportunistic infections, and cumulative mortality, and were more likely to require protease inhibitor-containing regimens or other more novel ART-based regimens.

Kericho CLinic-Based ART Diagnostic Evaluation (CLADE): Design, Accrual, and Baseline Characteristics of a Randomized Controlled Trial Conducted in Predominately Rural, District-Level, HIV Clinics of Kenya

BackgroundProspective clinical trial data regarding routine HIV-1 viral load (VL) monitoring of antiretroviral therapy (ART) in non-research clinics of Sub-Saharan Africa are needed for policy makers.Methods CLinic-based ART Diagnostic Evaluation (CLADE) is a randomized, controlled trial (RCT) evaluating feasibility, superiority, and cost-effectiveness of routine VL vs. standard of care (clinical and immunological) monitoring in adults initiating dual nucleoside reverse transcriptase inhibitor (NRTI)+non-NRTI ART. Participants were randomized (1:1) at 7 predominately rural, non-research, district-level clinics of western Kenya. Descriptive statistics present accrual patterns and baseline cohort characteristics.ResultsOver 15 months, 820 adults enrolled at 7 sites with 86–152 enrolled per site. Monthly site enrollment ranged from 2–92 participants. Full (100%) informed consent compliance was independently documented. Half (49.9%) had HIV diagnosed through voluntary counseling and testing. Study arms were similar: mostly females (57.6%) aged 37.6 (SD = 9.0) years with low CD4 (166 [SD = 106]) cells/m3). Notable proportions had WHO Stage III or IV disease (28.7%), BMI <18.5 kg/m2 (23.1%), and a history of tuberculosis (5.6%) or were receiving tuberculosis treatment (8.2%) at ART initiation. In the routine VL arm, 407/409 (99.5%) received baseline VL (234,577 SD = 151,055 copies/ml). All participants received lamivudine; 49.8% started zidovudine followed by 38.4% stavudine and 11.8% tenofovir; and, 64.4% received nevirapine as nNRTI (35.6% efavirenz).ConclusionsA RCT can be enrolled successfully in rural, non-research, resource limited, district-level clinics in western Kenya. Many adults presenting for ART have advanced HIV/AIDS, emphasizing the importance of universal HIV testing and linkage-to-care campaigns.Trial RegistrationClinicalTrials.gov NCT01791556

A randomized controlled trial of single-class maintenance therapy with abacavir/lamivudine/zidovudine after standard triple antiretroviral induction therapy: final 96-week results from the FREE study.

The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/μL and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA <50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/μL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59). For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA <400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and <50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA >400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

Rapid plasma viral suppression in naive HIV-infected patients with high CD4 cells and low viraemia initiating a dual nucleoside reverse transcriptase inhibitor strategy: a proof-of-concept study.

To evaluate whether a dual nucleoside reverse transcriptase inhibitor (NRTI) strategy can control HIV replication in antiviral therapy (ART)-naive HIV-infected patients with a high CD4 cell count and a low viral load (VL). This observational study included all HIV-infected treatment-naive patients with a CD4 cell count >300 cells/mm(3), a plasma HIV RNA between 1000 copies/mL and 30,000 copies/mL and wild-type virus who initiated dual NRTI ART between January 2008 and December 2012. HIV RNA and CD4 cell count were assessed at Day 0, Week (W) 4, W12, W24 and W48. The primary endpoint was the proportion of patients with a plasma VL (pVL) <50 copies/mL at W24. Twenty patients were included. The median (IQR) baseline characteristics were: time since HIV diagnosis, 25 months (8-66 months); CD4 cell count, 592 cells/mm(3) (405-798 cells/mm(3)); HIV RNA, 10,395 copies/mL (4106-16,566 copies/mL); and HIV DNA, 464 copies/10(6) peripheral blood mononuclear cells (195-1168 copies/10(6) PBMC). Nineteen patients received tenofovir/emtricitabine and one patient received abacavir/lamivudine. At W12, 88% of the patients with available data (n = 16/18, 95% CI 0.65-0.99) had a pVL <50 copies/mL. Overall, the proportion of patients with a pVL <50 copies/mL was 100% (n = 20/20, 95% CI 0.83-1.0) at W24 and 95% (n = 18/19, 95% CI 0.74-0.99) at W48 (with one patient lost to follow-up and one patient with poor treatment compliance). The median increase in CD4 cells was 83 cells/mm(3) (40-310 cells/mm(3)). There was no discontinuation of antiretroviral therapy for any reason such as lack of efficacy or toxicity. This pilot study suggests that, in patients with a high CD4 cell count and a low VL, a dual NRTI strategy may represent a potentially effective treatment strategy to control HIV replication. This needs to be confirmed in larger controlled clinical studies.

Clinical and virological response to antiretroviral drugs among HIV patients on first-line treatment in Dar-es-Salaam, Tanzania.

In Tanzania, the follow-up on antiretroviral therapy (ART) response is based on clinical outcomes. We investigated virological response and ARV resistance mutations in relation to clinical response in ARV-treated patients. A cross-sectional study of a cohort of 150 patients taking first-line ART in Dar-es-Salaam was conducted. Data were collected using standardized questionnaires and patients' blood samples. HIV viral load testing and genotyping was performed on all viremic samples. Statistical analyses compared clinical responders and non-responders. The median time on ART was 20 months; 71 (47%) patients were ART clinical responders. Clinical non-responders were more likely to have started ART with advanced disease with significantly lower median percentage weight gain (6% versus 20%) with respect to pre-treatment levels. Sixty-one (86%) and 64 (81%) of clinical responders and non-responders, respectively, had undetectable viral loads. Genotyping was successful in 24 (96%) virologically failing patients, among whom 83% had resistance mutations; 67% had dual nucleoside reverse transcriptase inhibitor (NRTI)/non-NRTI (NNRTI) resistance mutations. Seventeen (71%) and 19 (79%) patients had NRTI and NNRTI resistance mutations, respectively, which were related to the ART in use, with no difference between clinical responders and non-responders. The most prevalent subtypes were A and C, found in 9 (38%) and 7 (29%) patients, respectively. The observed virological response was high and did not correlate with clinical response. The prevalence of ARV resistance mutations was high in viraemic patients and was related to the ARV prescribed. We recommend use of viral load monitoring during ART in Tanzania.

Treatment as prevention in resource-limited settings: is it feasible to maintain HIV viral load suppression over time?

Recently, there has been increasing interest in the role of "treatment as prevention" (TasP). Some of the questions regarding TasP strategies arise from the perceived difficulties in achieving and maintaining viral load (VL) suppression over time and the risk of emergence of viral resistance that could compromise future treatment options. This study was conducted to assess these questions in a resource-limited setting. We performed a retrospective observational study of HIV-infected patients diagnosed in the pre-HAART era on follow-up at a private center from Buenos Aires, Argentina. Socio-demographic, clinical, and laboratory data were extracted from clinical charts. Analyses were performed to test for potential associations of selected variables with current virologic failure or use of third-line drugs. Of 619 patients on follow-up, 82 (13.2%) were diagnosed in the pre-HAART era. At the time of our study, 79 (96.3%) patients were on HAART, with a median duration of 14 years (IQR 12-15) of therapy, and exposure to mono or dual nucleoside reverse transcriptase inhibitors regimens in 47.8% of cases.Sixty-nine patients (87.3%) had undetectable VL, 37 (46.8%) never presented virologic failure, and 19 (24.1%) experienced only one failure. Thirteen patients (16.5%) were receiving third-line ART regimens, with an average of 2.7-fold more virologic failures than those on first- or second-line regimens (p = 0.007). Maintaining viral load suppression over time in resource-limited-settings is feasible.

Cytomegalovirus Viremia in Thai HIV-Infected Patients on Antiretroviral Therapy: Prevalence and Associated Mortality

Prevalence and risk factors of cytomegalovirus (CMV) viremia in patients infected with human immunodeficiency virus (HIV) starting antiretroviral therapy (ART) in developing countries are understudied. We measured CMV DNA in stored plasma specimens of 293 Thai HIV patients starting ART at CD4 counts <200 cells/mm(3). We examined Cox proportional hazard ratios (HRs) of 24 months mortality and new AIDS-defining illness (ADI). Of 293 patients, 159 (54.3%) were male. The median age was 33 years. The median baseline CD4 count was 82 cells/mm(3), and the median HIV-1 RNA was 4.9 log10 copies/mL. In total, 273 (93.2%) patients started potent combination ART, and 20 (6.8%) started dual nucleoside reverse transcriptase inhibitor (NRTI) therapy. CMV DNA was detected in 77 of 293 patients (26.3%) at baseline, and 9 of 199 patients with available specimen (4.5%) after 6 months of ART. The median CMV DNA was 548 copies/mL (interquartile range [IQR], 129-3849) at baseline and 114 copies/mL (IQR, 75-1099) at 6 months. In univariate analysis, death was associated with baseline CDC stage C, hemoglobin <10 g/dL, lower CD4 count, and CMV viremia. In multivariate analysis, only CMV DNA >500 copies/mL was significantly associated with mortality (HR: 7.28; 95% CI, 1.32-40.29, P = .023). CD4 count was the only variable associated with new ADI (HR: 0.70 per 50 CD4 cells increase; 95% CI, .49-.997, P = .048). In these Thai patients with advanced HIV disease, CMV viremia was frequent, and CMV DNA >500 copies/mL predicted increased mortality despite ART initiation. This calls for increased attention to screening of active CMV infection in advanced HIV patients in developing countries. Trials assessing preemptive anti-CMV therapy may be warranted.

Genetic Variants in the Host Restriction Factor APOBEC3G are Associated With HIV-1–Related Disease Progression and Central Nervous System Impairment in Children

Apolipoprotein B mRNA editing catalytic polypeptide 3G (APOBEC3G) protein is incorporated into nascent virus particles and mediates cytidine deamination (C-to-U) of first-strand reverse transcripts of HIV-1 in target cells resulting in G-to-A hypermutation of the coding strand and premature degradation. We investigated the effects of APOBEC3G genetic variants on HIV-1-related disease in children. APOBEC3G variants were detected using real-time polymerase chain reaction in HIV-1-infected children from Pediatric AIDS Clinical Trials Group (PACTG) protocols P152 and P300 that evaluated the effectiveness of 3 mono- or dual-nucleoside reverse transcriptase inhibitor treatments. Of the 1049 children evaluated, 60% were non-Hispanic black, 26% Hispanic, 13% non-Hispanic white, and 1% other or unknown race/ethnicity. Age ranged from 42 days to 18 years; 45% were males. APOBEC3G-H186R homozygous G/G genotype was associated with more rapid HIV-1 disease progression [hazard ratio (HR): 1.69; P = 0.01] and central nervous system (CNS) impairment (HR: 2.00; P = 0.02) compared with the wild-type A/A or heterozygous A/G genotype in a recessive model. In both additive and dominant models, APOBEC3G-F119F-C allele was associated with protection against disease progression (HR [additive]: 0.69; P = 0.002 and HR [dominant]: 0.60; P = 0.001, respectively) and CNS impairment (HR [additive]: 0.65; P = 0.02 and HR [dominant]: 0.54; P = 0.007, respectively). These associations remained significant in multivariate analyses controlling for baseline characteristics or previously identified genetic variants known to alter HIV-1-related disease in this cohort of children. APOBEC3G-H186R and F119F variants are associated with altered HIV-1-related disease progression and CNS impairment in children.

HIV Genotype Resistance Testing in Antiretroviral (ART) Exposed Indian Children—A Need of the Hour

Development of drug resistance in HIV infected children with treatment failure is a major impediment to selection of appropriate therapy. HIV genotype resistance assays predict drug resistance on the basis of mutations in the viral genome. However, their clinical utility, especially in a resource limited setting is still a subject of debate. The authors report two cases in which both the children suffered from treatment failure of various antiretroviral therapy regimes. In both the cases, Genotype Resistance Testing (GRT) prompted a radical change from proposed failure therapy as per existing guidelines. GRT was specifically important for the selection of a new dual Nucleoside reverse transcriptase inhibitors (NRTI) component of failure regimen by identifying TAMS and M184V mutations in the HIV genome. These case reports highlight the importance of GRT in children failing multiple antiretroviral regimes; and emphasizes the need to recognize situations where GRT is absolutely essential to guide appropriate therapy, even in a resource limited setting.

Management of HIV infection in treatment-naive patients: a review of the most current recommendations.

The most current guidelines issued by the Department of Health and Human Services (DHHS) on the management of human immunodeficiency virus (HIV) infection in treatment-naive patients are reviewed. Treatment guidelines are updated frequently because of the emergence of data demonstrating the risks and benefits of antiretroviral therapy. The DHHS guidelines strongly recommend initiating therapy in patients with certain conditions regardless of CD4 cell count and in patients with CD4 cell counts of <350 cells/mm(3). Although supporting data are less definitive, treatment is also recommended for patients with CD4 cell counts of 350-500 cells/mm(3). Treatment for patients with CD4 cell counts of >500 cells/mm(3) is controversial. Although cumulative observational data and biological evidence support treatment at higher CD4 cell counts, randomized controlled trial data to support this are not available, and the risk of antiretroviral toxicities, resistance, non-adherence, and cost should be considered in individual patients. The preferred regimens have been consolidated to four options, including a dual-nucleoside reverse transcriptase inhibitor backbone (tenofovir plus emtricitabine) with a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir plus ritonavir or darunavir plus ritonavir), or an integrase strand-transfer inhibitor (raltegravir). Regimens are classified as alternative or acceptable when they have potential safety or efficacy concerns, have higher pill burdens, or require more-frequent administration compared with preferred regimens. The DHHS 2011 guidelines advocate earlier antiretroviral therapy initiation than recommended in recent years, and preferred regimens have been refined to maximize efficacy, safety, and quality of life for treatment-naive HIV-infected patients.

Reduced Emergence of the M184V/I Resistance Mutation When Antiretroviral-Naïve Subjects Use Emtricitabine Versus Lamivudine in Regimens Composed of Two NRTIs Plus the NNRTI Efavirenz

Purpose: To compare the development of the M184V/I substitution among antiretroviral treatment-naïve patients taking the nucleoside reverse transcriptase inhibitors (NRTIs) emtricitabine (FTC) or lamivudine (3TC) from three phase 3 clinical trials of dual NRTIs (including either FTC or 3TC) plus the non-nucleoside reverse transcriptase inhibitor efavirenz (EFV). Methods: Study subjects from three phase 3 clinical trials (FTC 301A, GS-99-903, and GS-01-934) were classified as virologic failures (VF) if they had confirmed ≥400 copies/mL of HIV-1 RNA at week 48 or early study drug discontinuation. Subjects with VF were genotyped by population sequencing. The prevalence of the M184V/I substitution in the FTC or 3TC groups was analyzed using Fisher exact test and in multivariate logistic regression analyses. Results: Among the 3 trials, 522 subjects were treated with FTC dosed once daily and 841 subjects were treated with 3TC dosed twice daily. Among VF subjects at week 48, 5/26 (19.2%) FTC-treated subjects and 27/77 (35.5%) 3TC-treated subjects developed the M184V/I mutation (P = .145). Using the denominator of all subjects treated, 5/522 (1.0%) FTC-treated subjects versus 27/841 (3.2%) 3TC-treated subjects developed the M184V/I substitution (P = .009). Multivariate analyses adjusting for baseline viral load, baseline CD4 cell counts, and baseline NRTI resistance showed that treatment with FTC had a significantly lower rate of M184V/I development than treatment with 3TC (odds ratio 0.32; P = .02). Conclusions: The results of this pooled analysis of 3 clinical trials indicate a lower frequency of development of the M184V/I mutation in subjects treated with FTC versus 3TC when combined in regimens containing dual NRTIs and EFV.

Short Communication: Three Years Follow-Up of First-Line Antiretroviral Therapy in Cambodia: Negative Impact of Prior Antiretroviral Treatment

There are few long-term data on ART-experienced patients in resource-limited settings. We performed a cross-sectional study of HIV-infected patients included in the ESTHER program in Calmette hospital, Phnom Penh, Cambodia, after 36 ± 3 months of cART. Therapeutic, clinical, and immunovirological outcomes were compared between patients who stated they were ART-naive (naive group), dual nucleoside reverse-transcriptase inhibitor (two-NRTI group), or fixed-dose combination of stavudine/lamivudine/nevirapine experienced (three-drug group) at entry to the program. A logistic regression model was used to evaluate the factors associated with virological failure (PCR HIV > 250 copies/ml). Among the 256 patients included in the analysis, 148 (58%) were ART naive while 50 (20%) had previously received two NRTIs and 58 (22%) three drugs. At entry to the program, all the patients received two NRTIs and one nonnucleoside reverse-transcriptase inhibitor (NNRTI). At evaluation, 46 patients (18%) were switched to a protease inhibitor-based regimen (9%, 32%, and 29% of the naive, two-NRTI, and three-drug groups; p < 0.0001). The median CD4 cell count increase was 180/μl overall (IQR: 96-276) and was higher in ART-naive than ART-experienced patients. In the intent-to-treat analysis, virological success was achieved in 83.5%, 67%, and 69% of the naive, two-NRTI, and three-drug groups, respectively (p = 0.002). Factors associated with virological failure were suboptimal previous ART exposure and WHO immunological failure criteria. The long-term efficacy of first-line cART is maintained in Cambodia. In ART-experienced patients, viral load monitoring needs to be available to establish early virological failure and preserve the potency of second line regimens.