Subsequent Antiretroviral Therapy Research Articles

Mortality variability and differentials by age and causes of death in rural South Africa, 1994–2018

IntroductionUnderstanding mortality variability by age and cause is critical to identifying intervention and prevention actions to support disadvantaged populations. We assessed mortality changes in two rural South African populations over...

Point-of-care HIV diagnosis for infants: the outcomes we need to achieve

Caring for infants and young children living with HIV remains a reality for many families. Despite decades of work leading to a substantial reduction in vertical transmission rates, the stark reality of poor and often late access to HIV diagnosis and subsequent antiretroviral therapy (ART) remains an issue. This is especially true in the African region, where 90% of all HIV-exposed infants reside.1 150 000 children aged 0–9 years acquire HIV globally each year, but less than two-thirds access early infant testing services.

Analytical antiretroviral therapy interruption does not irreversibly change preinterruption levels of cellular HIV.

The impact of short-term analytical treatment interruptions (ATI) on the levels of cellular HIV and of residual activation after subsequent antiretroviral therapy (ART)-mediated plasma HIV viral load re-suppression remains under active investigation. Peripheral blood mononuclear cells (PBMC) from 23 ART-suppressed, chronically HIV-1-infected patients were evaluated at the initiation of an ATI, during ATI, and following plasma re-suppression of HIV with ART. T-cell activation was measured by flow cytometry. Total cellular HIV DNA, and episomal 2-long terminal repeat (2-LTR) circles were measured by droplet digital PCR (ddPCR). Cellular HIV multiply spliced RNA (tat/rev), unspliced (gag), and poly(A) tailed transcripts [poly(A)] were measured by reverse transcriptase-ddPCR. Analyses were performed using R version 2.5.1 or JMP Pro 11. ATI (median ATI duration, 4 weeks) resulted in a rise of plasma HIV RNA (median = 72900 copies/ml), decrease in CD4+ T cells/μl (median = 511.5 cells/μl; P = 0.0001), increase in T-cell activation, and increase in cellular HIV DNA and RNA. Mean fluorescence intensity of CD38 on CD4+HLA-DR+ T cells at baseline was positively associated with total HIV DNA levels during ATI (pol: P = 0.03, Rho = 0.44). Upon ART resumption, plasma HIV re-suppression occurred after a median of 13 weeks and resulted in restoration of pre-ATI CD4+ T cells/μl, T-cell activation, and levels of cellular HIV DNA and RNA. Monitored viremia and immune activation during an ATI in ART-suppressed chronic HIV-infected patients does not change the amount of persistent cellular HIV RNA or total HIV DNA after ART-mediated re-suppression.

Dendritic cell immunotherapy followed by cART interruption during HIV-1 infection induces plasma protein markers of cellular immunity and neutrophil recruitment.

ObjectivesTo characterize the host response to dendritic cell-based immunotherapy and subsequent combined antiretroviral therapy (cART) interruption in HIV-1-infected individuals at the plasma protein level.DesignAn autologous dendritic cell (DC) therapeutic vaccine was administered to HIV-infected individuals, stable on cART. The effect of vaccination was evaluated at the plasma protein level during the period preceding cART interruption, during analytical therapy interruption and at viral reactivation. Healthy controls and post-exposure prophylactically treated healthy individuals were included as controls.MethodsPlasma marker (‘analyte’) levels including cytokines, chemokines, growth factors, and hormones were measured in trial participants and control plasma samples using a multiplex immunoassay. Analyte levels were analysed using principle component analysis, cluster analysis and limma. Blood neutrophil counts were analysed using linear regression.ResultsPlasma analyte levels of HIV-infected individuals are markedly different from those of healthy controls and HIV-negative individuals receiving post-exposure prophylaxis. Viral reactivation following cART interruption also affects multiple analytes, but cART interruption itself only has only a minor effect. We find that Thyroxine-Binding Globulin (TBG) levels and late-stage neutrophil numbers correlate with the time off cART after DC vaccination. Furthermore, analysis shows that cART alters several regulators of blood glucose levels, including C-peptide, chromogranin-A and leptin. HIV reactivation is associated with the upregulation of CXCR3 ligands.ConclusionsChronic HIV infection leads to a change in multiple plasma analyte levels, as does virus reactivation after cART interruption. Furthermore, we find evidence for the involvement of TBG and neutrophils in the response to DC-vaccination in the setting of HIV-infection.

Clinical course and efficacy of antiretroviral therapy of combined bloodborne pathology: human immunodeficiency virus and chronic hepatitis C

Objective: To study the main epidemiological, clinical and laboratory features of the manifestations and course of hepatitis C and HIV infection as a mixed pathology, development and substantiation of epidemiological diagnosis algorithm, treatment and prevention. Materials and Methods. To perform this work, a clinical and laboratory examination of patients with HIV infection and chronic viral hepatitis C was carried out, who were observed at the AIDS Prevention and Control Center in Odessa in 2015–2016. All patients were examined clinically (complaints, anamnesis, history of life and epidemiological anamnesis, objective examination) and basic laboratory and instrumental investigetions, in accordance with the standards of patients with HIV infection examination. Three main clinical groups were identified: 1) patients with chronic viral hepatitis C (CVHC) – 41; 2) patients with HIV infection (HIV) – 58 people; 3) patients with mixed infection (HIV + CVHC) – 81 people. All patients with HIV infection were given treatment with Aluvia and Kaletra (lopinavir 200 mg and ritonavir 50 mg) 2 tablets twice a day (800/200 mg) orally. Results. Pre-existing viral liver disease increases the risk of potential hepatotoxicity of antiretroviral drugs realization; on the other hand, a number of drugs for HIV infection treatment may alter the pharmacokinetics of other drugs independently influencing on cytochrome P450, inhibiting or stimulating their activity. At the same time, the interaction of these drugs could be put to more profitable use in the combined therapy to maintain of antiretroviral medications appropriate plasma concentrations. Antiretroviral therapy for chronic hepatitis C and HIV-infected patients becomes important, due to the possibility of eradicating HCV infection, delayed progression of viral damage of the liver to prevent fibrosis, cirrhosis, decompensation development and onset of death. Conclusions. Early antiretroviral HCV therapy in co-infected patients due to the compensation of hepatic functions may improve the tolerability of subsequent antiretroviral therapy and reduce its hepatotoxic potential, thereby positively affecting the commitment of patients to treatment, improve the effectiveness of therapy by reducing the incidence of HIV-associated morbidity and mortality.

Metabolic Disorders in Patients with HIV

AbstractHuman Immunodeficiency Virus (HIV) infection and subsequent antiretroviral therapy (ART) are known to be related to different metabolic disorders. Although ART decreased HIV-associated mortality and morbidity, mortality rates in patients with HIV and ART are 3 to 15 higher than those in the general population. More than 50% of the mortality is due to diseases like: diabetes mellitus (DM), hypertension, cardiovascular diseases (CVD), chronic renal disease and complications following bone fractures. In patients with HIV the metabolic disorders are mainly caused by mithocondrial toxicity, a side effect of ART, and they are represented by: dyslipidemia, lipoatrophy, insulin resistance and diabetes mellitus.

Emerging antiretroviral drug resistance in sub-Saharan Africa: novel affordable technologies are needed to provide resistance testing for individual and public health benefits.

In industrialized countries, viral load monitoring and genotypic antiretroviral drug resistance testing (GART) play an important role in the selection of initial and subsequent combination antiretroviral therapy (cART) regimens. In contrast, resource constraints in Africa limit access to assays that could detect virologic failure, transmitted drug resistance (TDR) and acquired drug resistance to cART. This has adverse consequences for both individual and public health. Although the further roll-out of antiretrovirals for prevention, including preexposure prophylaxis (PrEP) and universal test and treat (UTT) strategies, could reduce HIV-1 incidence, these strategies may increase TDR [1,2]. Here, we present arguments that the scale up of antiretrovirals use should be accompanied by cost-effective assays for early detection of virologic failure, surveillance of TDR and GART for individual patient management.

Antiretroviral interventions for preventing breast milk transmission of HIV.

An estimated 260,000 children under the age of 15 years acquired HIV infection in 2012. As much as 42% of mother-to-child transmission is related to breastfeeding. Antiretroviral prophylaxis for mothers or infants has the potential to prevent mother-to-child transmission of HIV through breast milk. To determine which antiretroviral prophylactic regimens are efficacious and safe for reducing mother-to-child transmission of HIV through breastfeeding and thereby avert child morbidity and mortality. Using Cochrane Collaboration search methods in conjunction with appropriate search terms, we identified relevant studies from January 1, 1994 to January 14, 2014 by searching databases including Cochrane CENTRAL, EMBASE and PubMed, LILACS, and Web of Science/Web of Social Science. Randomized controlled trials in which HIV-infected mothers breastfed their infants, and in which the mothers used antiretroviral prophylaxis while breastfeeding their children or their children received antiretroviral prophylaxis for at least four weeks while breastfeeding, were included. Abstracts of all trials identified were examined independently by two authors. We identified 15,922 references and examined 81 in detail. Data were abstracted independently using a standardized form. Seven RCTs were included in the review.One trial compared triple antiretroviral prophylaxis during pregnancy and breastfeeding with short antiretroviral prophylaxis to given to the mother to prevent mother-to-child transmission of HIV. At 12 months, the risks of HIV transmission, and of HIV transmission or death, were lower, but there was no difference in infant mortality alone in the triple arm versus the short arm. Using the GRADE methodology, evidence quality for outcomes in this trial was generally low to moderate.One trial compared six months of breastfeeding using zidovudine, lamivudine, and lopinavir/ritonavir versus zidovudine, lamivudine, and abacavir from 26-34 weeks gestation. At six months, there was no difference in risk of infant HIV infection, infant death, or infant HIV infection or death between the two groups. Evidence quality for outcomes in this trial was generally very low to low.One trial of single dose nevirapine versus six weeks of infant zidovudine found the risk of HIV infection at 12 weeks to be greater in the zidovudine arm than in the single dose nevirapine arm. Evidence quality for outcomes in this trial was generally very low.One multi-country trial compared single dose nevirapine and six weeks of infant nevirapine. After 12 months, infants in the extended nevirapine group had a lower risk of infant mortality compared with the control. There was no difference in the risk of HIV infection or death or in HIV transmission alone in the extended nevirapine group compared with the control. Evidence quality for outcomes in this trial was generally low to moderate.One trial compared single dose nevirapine plus one week zidovudine; the control regimen plus nevirapine up to 14 weeks; or the control regimen with dual prophylaxis up to 14 weeks. At 24 months, the extended nevirapine regimen group had a lower risk of HIV transmission and of HIV transmission or death vs. the control. There was no difference in infant mortality alone. Compared with controls, the dual prophylaxis group had a lower risk of HIV transmission and of HIV transmission or death, but no difference in infant mortality alone. There was no difference in these outcomes between the two intervention arms. Evidence quality for outcomes in this trial was generally moderate to high.One trial compared six weeks of nevirapine with six months of nevirapine. Among infants of mothers not using highly active antiretroviral therapy, there was no difference in risk of HIV infection among the six month nevirapine group versus the six week nevirapine group. Evidence quality for outcomes in this trial was generally low to moderate.One trial compared a maternal triple-drug antiretroviral regimen, infant nevirapine, or neither intervention. Infants in the maternal prophylaxis arm were at lower risk for HIV, and HIV infection or death when compared with the control group. There was no difference in the risk of infant mortality alone. Infants with extended prophylaxis had a lower risk of HIV infection and of HIV infection or death versus the control group infants. There was no difference in the risk of infant mortality alone in the extended infant nevirapine group versus the control. There was no difference in HIV infection, infant mortality, and HIV infection or death between the maternal and extended infant prophylaxis groups. Evidence quality for outcomes in this trial was generally low to moderate. Antiretroviral prophylaxis, whether used by the HIV-infected mother or the HIV-exposed infant while breastfeeding, is efficacious in preventing mother-to-child transmission of HIV. Further research is needed regarding maternal resistance and response to subsequent antiretroviral therapy after maternal prophylaxis. An ongoing trial (IMPAACT 1077BF) compares the efficacy and safety of maternal triple antiretroviral prophylaxis versus daily infant nevirapine for prevention of mother-to-child transmission through breastfeeding.

Extensive Drug Resistance in HIV-Infected Cambodian Children Who Are Undetected as Failing First-Line Antiretroviral Therapy by WHO 2010 Guidelines

Antiretroviral therapy in resource-limited settings is monitored clinically and immunologically according to WHO guidelines. Frequent misclassification of virologic failure is reported, mostly in adults, leading to early therapy switch or late failure diagnosis. Pediatric treatment monitoring and resistance data upon first-line failure are limited, particularly when the 2010-WHO pediatric guidelines are used without routine viral load monitoring. We previously reported high treatment failure misclassification rates by pediatric 2010 guidelines in Cambodian children on first-line therapy. Here we determine the extent and patterns of resistance, with yearly viral load and 6-monthly CD4. Drug resistance mutations were determined using the IAS-USA 2011 list. Predicted resistance interpretation was determined with Stanford Database tools. Fifty-one children with available genotypes met inclusion criteria. All but one (subtype B) were CRF01_AE. The most common regimen was stavudine, lamivudine, and nevirapine (96%), taken for a median of 2.2 years. Resistance was seen in 98%; 96% to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs); 51% with ≥4 mutations. The most common NRTI mutations were 184V/I and 67N and the most common NNRTI mutations were 181C/Y/I/V and 190A/S. A total of 22% had multiresistant mutations and 18% had predicted high-level resistance to subsequent therapy options didanosine, abacavir, etravirine, and tenofovir. In 98% of Cambodian children misclassified as nonfailing first-line therapy by 2010 guidelines, 51% had extensive drug resistance to current and 18% to subsequent antiretroviral therapy. Affordable routine viral load monitoring allowing for early and more accurate treatment failure diagnosis is desperately needed in resource-limited settings.

HIV Drug Resistance in Mothers and Infants Following Use of Antiretrovirals to Prevent Mother-to-Child Transmission

The purpose of this article is to review prominent studies on HIV drug-resistance in mothers and their infants after the use of antiretroviral drugs to prevent mother-to-child-transmission in resource-limited communities. The effects of drug-resistance on subsequent combination antiretroviral therapy are discussed, as are the probable mechanisms of acquisition and decay or persistence of drug-resistant mutants. Differences in the rates of HIV drug-resistance from interventions used to prevent mother-to-child-transmission in North America and Europe are contrasted to the simplified regimens used in resource-limited settings. Unresolved issues related to HIV drug-resistance are reviewed, including: whether maternal zidovudine monotherapy selects significant resistance; the clinical relevance of HIV drug-resistant variants selected by single-dose nevirapine that persist as minority viral variants and can affect the outcome of non-nucleoside reverse transcriptase inhibitor-based therapy; and the use of maternal combination antiretroviral therapy during breastfeeding. Finally, the current and upcoming strategies to reduce HIV drug-resistance related to use of antiretrovirals to prevent mother-to-child-transmission are discussed and contrasted with the challenges of financing and administering antiretrovirals to prevent mother-to-child-transmission in resource-limited communities.

Evaluating the Effect of Early Versus Late ARV Regimen Change if Failure on an Initial Regimen: Results From the AIDS Clinical Trials Group Study A5095

The current goal of initial antiretroviral (ARV) therapy is suppression of plasma human immunodeficiency virus (HIV)-1 RNA levels to below 200 copies per milliliter. A proportion of HIV-infected patients who initiate antiretroviral therapy in clinical practice or antiretroviral clinical trials either fail to suppress HIV-1 RNA or have HIV-1 RNA levels rebound on therapy. Frequently, these patients have sustained CD4 cell counts responses and limited or no clinical symptoms and, therefore, have potentially limited indications for altering therapy which they may be tolerating well despite increased viral replication. On the other hand, increased viral replication on therapy leads to selection of resistance mutations to the antiretroviral agents comprising their therapy and potentially cross-resistance to other agents in the same class decreasing the likelihood of response to subsequent antiretroviral therapy. The optimal time to switch antiretroviral therapy to ensure sustained virologic suppression and prevent clinical events in patients who have rebound in their HIV-1 RNA, yet are stable, is not known. Randomized clinical trials to compare early versus delayed switching have been difficult to design and more difficult to enroll. In some clinical trials, such as the AIDS Clinical Trials Group (ACTG) Study A5095, patients randomized to initial antiretroviral treatment combinations, who fail to suppress HIV-1 RNA or have a rebound of HIV-1 RNA on therapy are allowed to switch from the initial ARV regimen to a new regimen, based on clinician and patient decisions. We delineate a statistical framework to estimate the effect of early versus late regimen change using data from ACTG A5095 in the context of two-stage designs. In causal inference, a large class of doubly robust estimators are derived through semiparametric theory with applications to missing data problems. This class of estimators is motivated through geometric arguments and relies on large samples for good performance. By now, several authors have noted that a doubly robust estimator may be suboptimal when the outcome model is misspecified even if it is semiparametric efficient when the outcome regression model is correctly specified. Through auxiliary variables, two-stage designs, and within the contextual backdrop of our scientific problem and clinical study, we propose improved doubly robust, locally efficient estimators of a population mean and average causal effect for early versus delayed switching to second-line ARV treatment regimens. Our analysis of the ACTG A5095 data further demonstrates how methods that use auxiliary variables can improve over methods that ignore them. Using the methods developed here, we conclude that patients who switch within 8 weeks of virologic failure have better clinical outcomes, on average, than patients who delay switching to a new second-line ARV regimen after failing on the initial regimen. Ordinary statistical methods fail to find such differences. This article has online supplementary material.

Circulating Nef Induces Dyslipidemia in Simian Immunodeficiency Virus–Infected Macaques by Suppressing Cholesterol Efflux

Human immunodeficiency virus (HIV) infection and subsequent antiretroviral therapy have been associated with an increased incidence of dyslipidemia and cardiovascular disease and has been shown to suppress cholesterol efflux from virus-infected macrophages by inducing Nef-dependent down-regulation of adenosine triphosphate-binding cassette transporter A1 (ABCA1). Here, the simian immunodeficiency virus (SIV)-infected macaque model was used to examine the consequences and mechanisms involved. SIV infection drove a significant remodeling of high-density lipoprotein profiles, suggesting that systemic inhibition of the ABCA1-dependent reverse cholesterol transport pathway occurred. The ABCA1 cholesterol transporter was significantly down-regulated in the livers of the SIV-infected macaques, and the viral protein Nef could be detected in the livers as well as in the plasma of infected animals. Extracellular myristoylated HIV Nef inhibited cholesterol efflux from macrophages and hepatocytes. Moreover, serum samples from SIV-infected macaques also suppressed cholesterol efflux in a Nef-dependent fashion. These results indicate that SIV infection is a significant contributor to primary dyslipidemia, likely through the ability of Nef to suppress ABCA1-dependent reverse cholesterol transport.

Detection of HIV-1 Drug Resistance in Women Following Administration of a Single Dose of Nevirapine: Comparison of Plasma RNA to Cellular DNA by Consensus Sequencing and by Oligonucleotide Ligation Assay

A single dose of nevirapine (sdNVP) to prevent mother-to-child transmission of HIV-1 increases the risk of failure of subsequent NVP-containing antiretroviral therapy (ART), especially when initiated within 6 months of sdNVP administration, emphasizing the importance of understanding the decay of nevirapine-resistant mutants. Nevirapine-resistant HIV-1 genotypes (with the mutations K103N, Y181C, and/or G190A) from 21 women were evaluated 10 days and 6 weeks after sdNVP administration and at the initiation of ART. Resistance was assayed by consensus sequencing and by a more sensitive assay (oligonucleotide ligation assay [OLA]) using plasma-derived HIV-1 RNA and cell-associated HIV-1 DNA. OLA detected nevirapine resistance in more specimens than consensus sequencing did (63% versus 33%, P<0.01). When resistance was detected only by OLA (n=45), the median mutant concentration was 18%, compared to 61% when detected by both sequencing and OLA (n=51) (P<0.0001). The proportion of women whose nevirapine resistance was detected by OLA 10 days after sdNVP administration was higher when we tested their HIV-1 RNA (95%) than when we tested their HIV-1 DNA (88%), whereas at 6 weeks after sdNVP therapy, the proportion was greater with DNA (85%) than with RNA (67%) and remained higher with DNA (33%) than with RNA (11%) at the initiation of antiretroviral treatment (median, 45 weeks after sdNVP therapy). Fourteen women started NVP-ART more than 6 months after sdNVP therapy; resistance was detected by OLA in 14% of the women but only in their DNA. HIV-1 resistance to NVP following sdNVP therapy persists longer in cellular DNA than in plasma RNA, as determined by a sensitive assay using sufficient copies of virus, suggesting that DNA may be superior to RNA for detecting resistance at the initiation of ART.

Study of the Genotypic Resistant Pattern in HIV-Infected Women and Children from Rural West Cameroon

The distribution of antiretroviral (ARV) therapy resistance mutations among HIV-1 strains was evaluated in 39 postpartum women, one pregnant woman, and 12 HIV-positive babies (seven newborns and five children) living in rural west Cameroon. Thirty-five women and all newborns received a single dose of nevirapine (NVP) to prevent mother-to-child transmission of HIV-1; two women were ARV treated and three were ARV naive. Of the 52 viral strains examined, three were subtype B, 45 were classified into eight HIV-1 non-B subtypes, and four remained unclassifiable. Sequence analysis for genotypic drug resistance in the reverse transcriptase (RT) gene showed the presence of mutations associated with nonnucleoside RT inhibitor resistance in 20% of the samples from NVP-treated women and in 57% of those from treated newborns. Mutations associated with nucleoside RT inhibitors (M184V in one case and V118I in four cases) were found in five samples, despite being derived from ARV-naive patients. As expected, a greater frequency of mutations was found in the protease gene region. Of the sequences analyzed, 79% harbored five to seven specific mutations. The secondary mutations showed the typical protease inhibitor resistance-associated pattern for non-subtype B viruses, M36I being the predominant mutation (92.5% in women, 100% in babies). Other mutations frequently detected were K20I, L63P, H69K, and I13V. These findings confirm that resistance mutations can be detected in ARV-naive patients infected with non-B subtypes and emphasize an urgent need for studies assessing the impact of these mutations on the efficacy of subsequent ARV therapy and on the appearance of drug-resistant strains.

Prophylactic antiretroviral regimens for prevention of mother-to-child transmission of HIV in resource-limited settings.

With the large international mobilization against HIV/AIDS, more HIV-infected people in resource-limited settings have access to antiretroviral therapy, including pregnant women. The relevance of simplified prophylactic antiretroviral regimens for the prevention of mother-to-child transmission of HIV may become questionable due to their lower efficacy and their higher risk of inducing viral resistance than fully suppressive antiretroviral therapy. Field implementation of current recommendations, impact of prophylactic regimens on subsequent antiretroviral therapy response and possible new indications of antiretroviral therapy in pregnant women will be reviewed in this paper. Prophylactic antiretroviral prevention of mother-to-child transmission regimens reached only 10% of the HIV-infected pregnant women in 2006, who were usually offered single-dose nevirapine only. The operational links between antenatal care and antiretroviral therapy programmes can now be documented and demonstrate good results in terms of safety and efficacy. The negative impact of single-dose nevirapine exposure on subsequent first-line antiretroviral therapy appears worse for mothers with advanced HIV disease at the time of delivery and short interval before antiretroviral therapy initiation. Strengthening the links between antenatal care and antiretroviral therapy programmes is critical for antiretroviral therapy-eligible HIV-infected pregnant women in terms of prevention of mother-to-child transmission and subsequent antiretroviral therapy response. The breastfeeding period could be a new indication for antiretroviral therapy in this population.

Walking the Tightrope in Prevention of Mother-to-Child Transmission of HIV Infection

A fine balance needs to be struck in our efforts to prevent pediatric HIV infection: the need for optimal regimens to drive down infection rates among infants must not compromise the therapeutic response of antiretroviral therapy in women when they eventually require it for their own health. Previous studies have demonstrated that 15%-69.5% of HIV-infected women will have resistance mutations to nevirapine (NVP) after its use in a singledose intervention to prevent mother-to-child transmission of HIV (MTCT). The occurrence of viral NVP resistance mutations has been found to reduce the response to NVP-containing regimens if initiated within 6 months after exposure to single-dose NVP. The acquisition of NVP resistance can be reduced substantially by using a zidovudine (ZDV) or lamivudine (3TC) tail for 4-7 days after delivery thereby preserving use of singledose NVP treatment in the intrapartum period for prevention of MTCT and in subsequent antiretroviral therapy. (excerpt)

Response to Antiretroviral Therapy after a Single, Peripartum Dose of Nevirapine

A single dose of nevirapine during labor reduces perinatal transmission of human immunodeficiency virus type 1 (HIV-1) but often leads to viral nevirapine resistance mutations in mothers and infants. We studied the response to nevirapine-based antiretroviral treatment among women and infants who had previously been randomly assigned to a single, peripartum dose of nevirapine or placebo in a trial in Botswana involving the prevention of the transmission of HIV-1 from mother to child. All women were treated with antenatal zidovudine. The primary end point for mothers and infants was virologic failure by the 6-month visit after initiation of antiretroviral treatment, estimated within groups by the Kaplan-Meier method. Of 218 women who started antiretroviral treatment, 112 had received a single dose of nevirapine and 106 had received placebo. By the 6-month visit after the initiation of antiretroviral treatment, 5.0% of the women who had received placebo had virologic failure, as compared with 18.4% of those who had received a single dose of nevirapine (P=0.002). Among 60 women starting antiretroviral treatment within 6 months after receiving placebo or a single dose of nevirapine, no women in the placebo group and 41.7% in the nevirapine group had virologic failure (P<0.001). In contrast, virologic failure rates did not differ significantly between the placebo group and the nevirapine group among 158 women starting antiretroviral treatment 6 months or more post partum (7.8% and 12.0%, respectively; P=0.39). Thirty infants also began antiretroviral treatment (15 in the placebo group and 15 in the nevirapine group). Virologic failure by the 6-month visit occurred in significantly more infants who had received a single dose of nevirapine than in infants who had received placebo (P<0.001). Maternal and infant findings did not change qualitatively by 12 and 24 months after the initiation of antiretroviral treatment. Women who received a single dose of nevirapine to prevent perinatal transmission of HIV-1 had higher rates of virologic failure with subsequent nevirapine-based antiretroviral therapy than did women without previous exposure to nevirapine. However, this applied only when nevirapine-based antiretroviral therapy was initiated within 6 months after receipt of a single, peripartum dose of nevirapine. (ClinicalTrials.gov number, NCT00197587 [ClinicalTrials.gov].).

Disease Progression Among HIV-Infected Children Who Receive Perinatal Zidovudine Prophylaxis

Studies of perinatal HIV infection have reported mixed results regarding the prognosis of HIV-infected infants exposed to perinatal zidovudine prophylaxis (PZP). We have followed a population-based cohort of children with perinatal HIV infection to evaluate whether early HIV disease progression was more common among those who received PZP and whether subsequent antiretroviral therapy (ART) was less effective in preventing early disease progression. We identified 73 children with perinatal HIV infection born between 1994 and 2001 with at least 3 years of follow-up and with information concerning PZP administration. Children who received PZP started subsequent ART at an earlier age than those who did not receive PZP (median age at starting treatment: 2 months for PZP vs. 6 months for no PZP; P = 0.0002). PZP was associated with decreased early HIV progression: 21% (7 of 33) of children who received PZP progressed to a category C diagnosis by 3 years compared with 45% (18 of 40) of children who did not receive PZP (P = 0.047). Children who did not receive PZP progressed to a category C diagnosis at a younger age than children who received PZP (median: 4 vs. 11 months; P = 0.061). ART was as effective in preventing early HIV progression in children who received PZP as in children who did not receive PZP. In our population-based cohort of perinatally HIV-infected children, those who received PZP started ART at a significantly earlier age than those who did not receive PZP and also demonstrated decreased HIV disease progression by the age of 3 years.

Differential Impact of Thymidine Analogue Mutations on Emtricitabine and Lamivudine Susceptibility

The impact of drug resistance-associated mutations on subsequent antiretroviral therapy is an important consideration in managing treatment-experienced, HIV-1-infected patients. Lamivudine (3TC) and emtricitabine (FTC) are structurally related nucleoside reverse transcriptase inhibitors (NRTIs) approved for use in HIV-1-infected individuals. To evaluate whether susceptibility differences exist between lamivudine and emtricitabine, the phenotypic impact of common NRTI resistance-associated mutations was compared in HIV-1 from patient samples with paired FTC and 3TC susceptibility results. FTC phenotypic susceptibility was more greatly impacted than 3TC susceptibility in the presence of thymidine analogue mutations (TAMs), as the mean fold-change values were higher for FTC than for 3TC in groups of samples containing TAMs (P < 0.001 for 6 of 7 groups). For samples with K65R, L74I/V, or Q151M mutations, the phenotypic impact was similar, as the mean fold-change was not significantly different between drugs. Although the long-term clinical significance of these differences is unclear, they may suggest differential efficacy in some patients with prior NRTI experience, especially those with HIV harboring TAMs.

Persistence of nevirapine-resistant HIV-1 in women after single-dose nevirapine therapy for prevention of maternal-to-fetal HIV-1 transmission.

Single-dose nevirapine (sdNVP) for prevention of mother-to-child transmission of HIV-1 can select nevirapine (NVP)-resistant variants, but the frequency, duration, and clinical significance of this resistance is not well defined. We used a sensitive allele-specific PCR assay to assess the emergence and persistence of NVP-resistant variants in plasma samples from 22 women with HIV-1 subtype C infection who participated in a study of sdNVP for prevention of mother-to-child transmission of HIV-1. The women were categorized into three groups on the basis of detection of NVP resistance by standard genotype analysis. Group 1 (n = 6) had NVP resistance detected at 2 and 6 mo after sdNVP, but not at 12 mo. Group 2 (n = 9) had NVP resistance detected at 2 mo, but not 6 mo. Group 3 (n = 7) had no NVP resistance detected at any time point. Allele-specific PCR analysis for the two most common NVP resistance mutations (K103N and Y181C) detected NVP-resistant variants in most (16 of 21) samples that were negative for NVP resistance by standard genotype, at levels ranging from 0.1% to 20% 1 yr after treatment. The frequency of NVP-resistant mutations decreased over time, but persisted above predose levels for more than 1 yr in > or = 23% of the women. These findings highlight the urgent need for studies assessing the impact of sdNVP on the efficacy of subsequent antiretroviral therapy containing NVP or other nonnucleoside reverse transcriptase inhibitors.