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1.  Nucleoside Reverse Transcriptase Inhibitor Resistance Mutations Associated with First-Line Stavudine-Containing Antiretroviral Therapy: Programmatic Implications for Countries Phasing Out Stavudine 
The Journal of Infectious Diseases  2013;207(Suppl 2):S70-S77.
Background
The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure.
Methods
We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance.
Results
Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M.
Conclusions
Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.
doi:10.1093/infdis/jit114
PMCID: PMC3657117  PMID: 23687292
HIV-1; drug resistance; mutations; nucleoside reverse transcriptase inhibitor; NRTI; stavudine; d4T; zidovudine; AZT; tenofovir; TDF; subtypes
2.  Prevalence, Risk Factors, and Impact of Isolated Antibody to Hepatitis B Core Antigen and Occult Hepatitis B Virus Infection in HIV-1–Infected Pregnant Women 
Among hepatitis B (HB) surface antigen–negative/human immunodeficiency virus–infected pregnant women in Thailand, 14% had isolated antibody to HB core antigen (anti-HBc); of whom 24% had occult HB virus (HBV) infection with low HBV DNA levels. None transmitted HBV to their infants.
Background. Prevalence and risk factors for isolated antibody to hepatitis B core antigen (anti-HBc) and occult hepatitis B virus (HBV) infection are not well known in human immunodeficiency virus type 1 (HIV-1)–infected pregnant women. It is unclear if women with occult infections are at risk of transmitting HBV to their infants.
Methods. HIV-1–infected and HBV surface antigen (HBsAg)–negative pregnant women were tested for antibody to HBsAg (anti-HBs) and anti-HBc using enzyme immunoassay. Women with isolated anti-HBc were assessed for occult HBV infection, defined as HBV DNA levels >15 IU/mL, using the Abbott RealTime HBV DNA assay. Infants born to women with isolated anti-HBc and detectable HBV DNA were tested at 4 months of age for HBV DNA. Logistic regression analysis was used to identify factors associated with isolated anti-HBc and occult HBV infection.
Results. Among 1812 HIV-infected pregnant women, 1682 were HBsAg negative. Fourteen percent (95% confidence interval [CI], 12%–15%) of HBsAg-negative women had an isolated anti-HBc that was independently associated with low CD4 count, age >35 years, birth in northern Thailand, and positive anti–hepatitis C virus serology. Occult HBV infection was identified in 24% (95% CI, 18%–30%) of women with isolated anti-HBc, representing 2.6% (95% CI, 1.9%–3.5%) of HIV-1–infected pregnant women, and was inversely associated with HIV RNA levels. None of the women with isolated anti-HBc and occult HBV infection transmitted HBV to their infants.
Conclusions. HIV-1–infected pregnant women with isolated anti-HBc and occult HBV infection have very low HBV DNA levels and are thus at very low risk to transmit HBV to their infants.
doi:10.1093/cid/cit166
PMCID: PMC3707427  PMID: 23487379
HIV-1–infected pregnant women; isolated anti-HBc; occult HBV infection; perinatal transmission
3.  Estimating the Timing of Mother-to-Child Transmission of the Human Immunodeficiency Virus Type 1 Using a Viral Molecular Evolution Model 
PLoS ONE  2014;9(4):e90421.
Background
Mother-to-child transmission (MTCT) is responsible for most pediatric HIV-1 infections worldwide. It can occur during pregnancy, labor, or breastfeeding. Numerous studies have used coalescent and molecular clock methods to understand the epidemic history of HIV-1, but the timing of vertical transmission has not been studied using these methods. Taking advantage of the constant accumulation of HIV genetic variation over time and using longitudinally sampled viral sequences, we used a coalescent approach to investigate the timing of MTCT.
Materials and Methods
Six-hundred and twenty-two clonal env sequences from the RNA and DNA viral population were longitudinally sampled from nine HIV-1 infected mother-and-child pairs [range: 277–1034 days]. For each transmission pair, timing of MTCT was determined using a coalescent-based model within a Bayesian statistical framework. Results were compared with available estimates of MTCT timing obtained with the classic biomedical approach based on serial HIV DNA detection by PCR assays.
Results
Four children were infected during pregnancy, whereas the remaining five children were infected at time of delivery. For eight out of nine pairs, results were consistent with the transmission periods assessed by standard PCR-based assay. The discordance in the remaining case was likely confused by co-infection, with simultaneous introduction of multiple maternal viral variants at the time of delivery.
Conclusions
The study provided the opportunity to validate the Bayesian coalescent approach that determines the timing of MTCT of HIV-1. It illustrates the power of population genetics approaches to reliably estimate the timing of transmission events and deepens our knowledge about the dynamics of viral evolution in HIV-infected children, accounting for the complexity of multiple transmission events.
doi:10.1371/journal.pone.0090421
PMCID: PMC3981669  PMID: 24717647
4.  Cost-Effectiveness of Early Infant HIV Diagnosis of HIV-Exposed Infants and Immediate Antiretroviral Therapy in HIV-Infected Children under 24 Months in Thailand 
PLoS ONE  2014;9(3):e91004.
Background
HIV-infected infants have high risk of death in the first two years of life if untreated. WHO guidelines recommend early infant HIV diagnosis (EID) of all HIV-exposed infants and immediate antiretroviral therapy (ART) in HIV-infected children under 24-months. We assessed the cost-effectiveness of this strategy in HIV-exposed non-breastfed children in Thailand.
Methods
A decision analytic model of HIV diagnosis and disease progression compared: EID using DNA PCR with immediate ART (Early-Early); or EID with deferred ART based on immune/clinical criteria (Early-Late); vs. clinical/serology based diagnosis and deferred ART (Reference). The model was populated with survival and cost data from a Thai observational cohort and the literature. Incremental cost-effectiveness ratio per life-year gained (LYG) was compared against the Reference strategy. Costs and outcomes were discounted at 3%.
Results
Mean discounted life expectancy of HIV-infected children increased from 13.3 years in the Reference strategy to 14.3 in the Early-Late and 17.8 years in Early-Early strategies. The mean discounted lifetime cost was $17,335, $22,583 and $29,108, respectively. The cost-effectiveness ratio of Early-Late and Early-Early strategies was $5,149 and $2,615 per LYG, respectively as compared to the Reference strategy. The Early-Early strategy was most cost-effective at approximately half the domestic product per capita per LYG ($4,420 in Thailand 2011). The results were robust in deterministic and probabilistic sensitivity analyses including varying perinatal transmission rates.
Conclusion
In Thailand, EID and immediate ART would lead to major survival benefits and is cost- effective. These findings strongly support the adoption of WHO recommendations as routine care.
doi:10.1371/journal.pone.0091004
PMCID: PMC3954590  PMID: 24632750
5.  Analysis of residual perinatal transmission of hepatitis B virus (HBV) and of genetic variants in human immunodeficiency virus and HBV co-infected women and their offspring 
Background
Despite implementation of universal infant hepatitis B (HB) vaccination, mother-to-child transmission (MTCT) of hepatitis B virus (HBV) still occurs. Limited data are available on the residual MTCT of HBV in human immunodeficiency virus (HIV)-HBV co-infected women.
Objectives
We assessed the prevalence of HBV infection among HIV-infected pregnant women and the rate of residual MTCT of HBV from HIV-HBV co-infected women and analyzed the viral determinants in mothers and their HBV-infected children.
Study design
HIV-1 infected pregnant women enrolled in two nationwide perinatal HIV prevention trials in Thailand were screened for HB surface antigen (HBsAg) and tested for HBeAg and HBV DNA load. Infants born to HBsAg-positive women had HBsAg and HBV DNA tested at 4–6 months. HBV diversity within each HBV-infected mother-infant pair was analyzed by direct sequencing of amplified HBsAg-encoding gene and cloning of amplified products.
Results
Among 3,312 HIV-1 infected pregnant women, 245 (7.4%) were HBsAg-positive, of whom 125 were HBeAg-positive. Of 230 evaluable infants born to HBsAg-positive women, 11 (4.8%) were found HBsAg and HBV DNA positive at 4–6 months; 8 were born to HBeAg-positive mothers. HBV genetic analysis was performed in 9 mother-infant pairs and showed that 5 infants were infected with maternal HBV variants harboring mutations within the HBsAg “a” determinant, and four were infected with wild-type HBV present in highly viremic mothers.
Conclusions
HBV-MTCT still occurs when women have high HBV DNA load and/or are infected with HBV variants. Additional interventions targeting highly viremic women are thus needed to reduce further HBV-MTCT.
doi:10.1016/j.jcv.2013.06.025
PMCID: PMC3872003  PMID: 23916828
HBs antigen variants; Hepatitis B vaccine failure; HIV pregnant women; mother-to-child transmission; Thailand
6.  Switching HIV Treatment in Adults Based on CD4 Count Versus Viral Load Monitoring: A Randomized, Non-Inferiority Trial in Thailand 
PLoS Medicine  2013;10(8):e1001494.
Using a randomized controlled trial, Marc Lallemant and colleagues ask if a CD4-based monitoring and treatment switching strategy provides a similar clinical outcome compared to the standard viral load-based strategy for adults with HIV in Thailand.
Please see later in the article for the Editors' Summary
Background
Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand.
Methods and Findings
The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50–250/mm3) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm3. The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6–11.4) in VL versus 7.4% (5.1–10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2–8.4) in VL versus 7.5% (5.0–11.1) in CD4 (p = 0.097). Median time from treatment initiation to switch was 11.7 months (7.7–19.4) in VL and 24.7 months (15.9–35.0) in CD4 (p = 0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8–8.0) in VL versus 15.8 months (8.5–20.4) in CD4 (p = 0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported.
Conclusions
The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings.
Trial registration
ClinicalTrials.gov NCT00162682
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (most of them living in low-and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV infection leads to the destruction of immune system cells (including CD4 cells, a type of white blood cell), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (HAART)—combined drugs regimens that suppress viral replication and allow restoration of the immune system—became available. For people living in affluent countries, HIV/AIDS became a chronic condition but, because HAART was expensive, HIV/AIDS remained a fatal illness for people living in resource-limited countries. In 2003, the international community declared HIV/AIDS a global health emergency and, in 2006, it set the target of achieving universal global access to HAART by 2010. By the end of 2011, 8 million of the estimated 14.8 million people in need of HAART in low- and middle-income countries were receiving treatment.
Why Was This Study Done?
At the time this trial was conceived, national and international recommendations were that HIV-positive individuals should start HAART when their CD4 count fell below 200 cells/mm3 and should have their CD4 count regularly monitored to optimize HAART. In 2013, the World Health Organization (WHO) recommendations were updated to promote expanded eligibility for HAART with a CD4 of 500 cells/mm3 or less for adults, adolescents, and older children although priority is given to individuals with CD4 count of 350 cells/mm3 or less. Because HIV often becomes resistant to first-line antiretroviral drugs, WHO also recommends that viral load—the amount of virus in the blood—should be monitored so that suspected treatment failures can be confirmed and patients switched to second-line drugs in a timely manner. This monitoring and switching strategy is widely used in resource-rich settings, but is still very difficult to implement for low- and middle-income countries where resources for monitoring are limited and access to costly second-line drugs is restricted. In this randomized non-inferiority trial, the researchers compare the performance of a CD4-based treatment monitoring and switching strategy with the standard viral load-based strategy among HIV-positive adults in Thailand. In a randomized trial, individuals are assigned different interventions by the play of chance and followed up to compare the effects of these interventions; a non-inferiority trial investigates whether one treatment is not worse than another.
What Did the Researchers Do and Find?
The researchers assigned about 700 HIV-positive adults who were beginning HAART for the first time to have their CD4 count (CD4 arm) or their CD4 count and viral load (VL arm) determined every 3 months. Participants were switched to a second-line therapy if their CD4 count declined by more than 30% from their peak CD4 count (CD4 arm) or if a viral load of more than 400 copies/ml was recorded (VL arm). The 3-year cumulative risk of clinical failure (defined as death, a new AIDS-defining event, or a CD4 count of less than 50 cells/mm3) was 8% in the VL arm and 7.4% in the CD4 arm. This difference in clinical failure risk met the researchers' predefined criterion for non-inferiority. The probability of a treatment switch was similar in the two arms, but the average time from treatment initiation to treatment switch and the average duration of a high viral load after treatment switch were both longer in the CD4 arm than in the VL arm. Finally, the future-drug-option score, a measure of viral drug resistance profiles, was similar in the two arms at the time of treatment switch.
What Do These Findings Mean?
These findings suggest that, in Thailand, a CD4 switching strategy is non-inferior in terms of clinical outcomes among HIV-positive adults 3 years after beginning HAART when compared to the recommended viral load-based switching strategy and that there is no difference between the strategies in terms of viral suppression and immune restoration after 3-years follow-up. Importantly, however, even though patients in the CD4 arm spent longer with a high viral load than patients in the VL arm, the emergence of HIV mutants resistant to antiretroviral drugs was similar in the two arms. Although these findings provide no information about the long-term outcomes of the two monitoring strategies and may not be generalizable to routine care settings, they nevertheless provide reassurance that using CD4 counts alone to monitor HAART in HIV treatment programs in resource-limited settings is an appropriate strategy to use as viral load measurement becomes more affordable and feasible in these settings.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001494.
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its 2010 recommendations for antiretroviral therapy for HIV infection in adults and adolescents are available as well as the June 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the global HIV/AIDS epidemic, on HIV and AIDS in Thailand, on universal access to AIDS treatment, and on starting, monitoring and switching HIV treatment (in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about HIV and AIDS
More information about this trial (the PHPT-3 trial) is available
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about HIV treatment
doi:10.1371/journal.pmed.1001494
PMCID: PMC3735458  PMID: 23940461
7.  Plasma Drug Concentrations and Virologic Evaluations after Stopping Treatment with Nonnucleoside Reverse-Transcriptase Inhibitors in HIV Type 1–Infected Children 
Background
The optimum strategy for stopping treatment with drugs that have different half-lives in a combination regimen to minimize the risk of selecting drug-resistant viruses remains unknown. We evaluated drug concentrations in plasma, human immunodeficiency virus (HIV) load, and development of drug resistance after a planned treatment interruption of a nonnucleoside reverse-transcriptase inhibitor (NNRTI)–containing regimen in HIV type 1–infected children.
Methods
Children with viral loads <50 copies/mL and CD4 cell percentages ≥30% (for children aged 2–6 years) or CD4 cell percentages ≥25% and CD4 cell counts ≥500 cells/μL (for children aged 7–15 years) were randomized to either a planned treatment interruption or to continuous therapy. In the planned treatment interruption arm, either (1) treatment with nevirapine or efavirenz was stopped, and treatment with the remaining drugs was continued for 7–14 days, or (2) nevirapine or efavirenz were replaced by a protease inhibitor, and all drugs were stopped after 7–14 days. Sampling for determination of plasma drug concentrations, measurement of viral load, and drug resistance testing was scheduled at day 0, day 7 (drug concentrations only), day 14, and day 28 after interruption of treatment with an NNRTI.
Results
Treatment with an NNRTI was interrupted for 35 children (20 were receiving nevirapine, and 15 were receiving efavirenz). Median time from NNRTI cessation to stopping all drugs was 9 days (range, 6–15 days) for nevirapine and 14 days (range, 6–18 days) for efavirenz. At 7 days, 1 (5%) of 19 and 4 (50%) of 8 children had detectable nevirapine and efavirenz concentrations, respectively; efavirenz remained detectable in 3 (25%) of 12 children at 14 days. At 14 days, viral load was ≥50 copies/mL in 6 of 16 children interrupting treatment with nevirapine (range, 52–7000 copies/mL) and in 2 of 12 children interrupting treatment with efavirenz (range, 120–1600 copies/mL). No new NNRTI mutations were observed.
Conclusions
In children with virological suppression who experienced interruption of treatment with an NNRTI, staggered or replacement stopping strategies for a median of 9 days for nevirapine and 14 days for efavirenz were not associated with the selection of NNRTI resistance mutations.
doi:10.1086/587657
PMCID: PMC3597130  PMID: 18419497
8.  Laboratory and Clinical Predictors of Disease Progression following Initiation of Combination Therapy in HIV-Infected Adults in Thailand 
PLoS ONE  2012;7(8):e43375.
Background
Data on determinants of long-term disease progression in HIV-infected patients on antiretroviral therapy (ART) are limited in low and middle-income settings.
Methods
Effects of current CD4 count, viral load and haemoglobin and diagnosis of AIDS-defining events (ADEs) after start of combination ART (cART) on death and new ADEs were assessed using Poisson regression, in patient aged ≥18 years within a multi-centre cohort in Thailand.
Results
Among 1,572 patients, median follow-up from cART initiation was 4.4 (IQR 3.6–6.3) years. The analysis of death was based on 60 events during 6,573 person-years; 30/50 (60%) deaths with underlying cause ascertained were attributable to infections. Analysis of new ADE included 192 events during 5,865 person-years; TB and Pneumocystis jiroveci pneumonia were the most commonly presented first new ADE (35% and 20% of cases, respectively). In multivariable analyses, low current CD4 count after starting cART was the strongest predictor of death and of new ADE. Even at CD4 above 200 cells/mm3, survival improved steadily with CD4, with mortality rare at ≥500 cells/mm3 (rate 1.1 per 1,000 person-years). Haemoglobin had a strong independent effect, while viral load was weakly predictive with poorer prognosis only observed at ≥100,000 copies/ml. Mortality risk increased following diagnosis of ADEs during cART. The decline in mortality rate with duration on cART (from 21.3 per 1,000 person-years within first 6 months to 4.7 per 1,000 person-years at ≥36 months) was accounted for by current CD4 count.
Conclusions
Patients with low CD4 count or haemoglobin require more intensive diagnostic and treatment of underlying causes. Maintaining CD4≥500 cells/mm3 minimizes mortality. However, patient monitoring could potentially be relaxed at high CD4 count if resources are limited. Optimal ART monitoring strategies in low-income settings remain a research priority. Better understanding of the aetiology of anaemia in patients on ART could guide prevention and treatment.
doi:10.1371/journal.pone.0043375
PMCID: PMC3419679  PMID: 22905264
9.  Long-Term Hepatitis B Virus (HBV) Response to Lamivudine-Containing Highly Active Antiretroviral Therapy in HIV-HBV Co-Infected Patients in Thailand 
PLoS ONE  2012;7(7):e42184.
Background
Approximately 4 million of people are co-infected with HIV and Hepatitis B virus (HBV). In resource-limited settings, the majority of HIV-infected patients initiate first-line highly active antiretroviral therapy containing lamivudine (3TC-containing-HAART) and long-term virological response of HBV to lamivudine-containing HAART in co-infected patients is not well known.
Methodology/Principal Finding
HIV-HBV co-infected patients enrolled in the PHPT cohort (ClinicalTrials.gov NCT00433030) and initiating a 3TC-containing-HAART regimen were included. HBV-DNA, HIV-RNA, CD4+ T-cell counts and alanine transaminase were measured at baseline, 3 months, 12 months and then every 6 months up to 5 years. Kaplan-Meier analysis was used to estimate the cumulative rates of patients who achieved and maintained HBV-DNA suppression. Of 30 co-infected patients, 19 were positive for HBe antigen (HBeAg). At initiation of 3TC-containing-HAART, median HBV DNA and HIV RNA levels were 7.35 log10 IU/mL and 4.47 log10 copies/mL, respectively. At 12 months, 67% of patients achieved HBV DNA suppression: 100% of HBeAg-negative patients and 47% of HBeAg-positive. Seventy-three percent of patients had HIV RNA below 50 copies/mL. The cumulative rates of maintained HBV-DNA suppression among the 23 patients who achieved HBV-DNA suppression were 91%, 87%, and 80% at 1, 2, and 4 years respectively. Of 17 patients who maintained HBV-DNA suppression while still on 3TC, 4 (24%) lost HBsAg and 7 of 8 (88%) HBeAg-positive patients lost HBeAg at their last visit (median duration, 59 months). HBV breakthrough was observed only in HBeAg-positive patients and 6 of 7 patients presenting HBV breakthrough had the rtM204I/V mutations associated with 3TC resistance along with rtL180M and/or rtV173L.
Conclusions
All HBeAg-negative patients and 63% of HBeAg-positive HIV-HBV co-infected patients achieved long-term HBV DNA suppression while on 3TC-containing-HAART. This study provides information useful for the management of co-infected patients in resource-limited countries where the vast majority of co-infected patients are currently receiving 3TC.
doi:10.1371/journal.pone.0042184
PMCID: PMC3409123  PMID: 22860080
10.  Adherence to Antiretroviral Therapy and Acceptability of Planned Treatment Interruptions in HIV-Infected Children 
AIDS and Behavior  2012;17(1):193-202.
There have been no paediatric randomised trials describing the effect of planned treatment interruptions (PTIs) of antiretroviral therapy (ART) on adherence, or evaluating acceptability of such a strategy. In PENTA 11, HIV-infected children were randomised to CD4-guided PTIs (n = 53) or continuous therapy (CT, n = 56). Carers, and children if appropriate, completed questionnaires on adherence to ART and acceptability of PTIs. There was no difference in reported adherence on ART between CT and PTI groups; non-adherence (reporting missed doses over the last 3 days or marking <100 % adherence since the last clinical visit on a visual analogue scale) was 18 % (20/111) and 14 % (12/83) on carer questionnaires in the CT and PTI groups respectively (odds ratios, OR (95 % CI) = 1.04 (0.20, 5.41), χ2 (1) = 0.003, p = 0.96). Carers in Europe/USA reported non-adherence more often (31/121, 26 %) than in Thailand (1/73, 1 %; OR (95 % CI) = 54.65 (3.68, 810.55), χ2 (1) = 8.45, p = 0.004). The majority of families indicated they were happy to have further PTIs (carer: 23/36, 64 %; children: 8/13, 62 %), however many reported more clinic visits during PTI were a problem (carer: 15/36, 42 %; children: 6/12, 50 %).
doi:10.1007/s10461-012-0197-y
PMCID: PMC3548111  PMID: 22584916
Adherence; Acceptability; Planned treatment interruptions; HIV; Children
11.  Influence of body weight on achieving indinavir concentrations within its therapeutic window in HIV-infected Thai patients receiving indinavir boosted with ritonavir 
Therapeutic drug monitoring  2011;33(1):25-31.
Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a non-linear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics was best described by a one compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance (CL/F) and volume of distribution (Vd/F) and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir CL/F and Vd/F were 21.3 L/h/70kg (30%) and 90.7 L/70kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration > 0.1 mg/L was >99% for 600/100 mg and >98% for 400/100 mg, twice daily, in patients 40–80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (>10.0 mg/L), increased from 1% to 10% with 600/100 mg, compared to <1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients <50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity.
doi:10.1097/FTD.0b013e3182057f6f
PMCID: PMC3058116  PMID: 21233689
HIV-1; Highly Active Antiretroviral Therapy; Indinavir; Thai patient population; therapeutic drug monitoring
12.  Long-Term Survival of HIV-Infected Children Receiving Antiretroviral Therapy in Thailand: A 5-Year Observational Cohort Study 
Background. There are scarce data on the long-termsurvival of human immunodeficiency virus (HIV)—infected children receiving antiretroviral therapy (ART) in lower-middle income countries beyond 2 years of follow-up.
Methods. Previously untreated children who initiated ART on meeting immunological and/or clinical criteria were followed in a prospective cohort in Thailand. The probability of survival up to 5 years from initiation was estimated using Kaplan-Meier methods, and factors associated with mortality were assessed using Cox regression analyses.
Results. Five hundred seventy-eight children received ART; of these, 111 (19.2%) were followed since birth. At start of ART (baseline), the median age was 6.7 years, 128 children (22%) were aged <2 years, and the median CD4 cell percentage was 7%. Median duration of follow-up was 53 months; 42 children (7%) died, and 38 (7%) were lost to follow-up. Age <12 months, low CD4 cell percentage, and low weight-for-height z score at ART initiation were independently associated with mortality (P < .001). The probability of survival among infants aged <12 months at baseline was 84.3% at 1 year and 76.7% at 5 years of ART, compared with 95.7% and 94.8%, respectively, among children aged ⩾1 year. Low CD4 cell percentage and wasting at baseline had a strong association with mortality among older children but weak or no association among infants.
Conclusions. Children who initiated ART as infants after meeting immunological and/or clinical criteria had a high risk of mortality which persisted beyond the first year of therapy. Among older children, those with severe wasting or low CD4 cell percentage at treatment initiation were at high risk of mortality during the first 6 months of therapy. These findings support the scale-up of early HIV diagnosis and immediate treatment in infants, before advanced disease progression in older children.
doi:10.1086/657401
PMCID: PMC3106246  PMID: 21054181
13.  The interrelated transmission of human immunodeficiency virus type 1 and cytomegalovirus during gestation and delivery in the offspring of HIV-infected mothers 
Our objective was to analyze, in formula-fed infants, correlates of HIV mother-to-child transmission, including cytomegalovirus (CMV) infection.
HIV-infected infants were matched with HIV-uninfected by maternal HIV RNA in a case-control design. Infant CMV infection was determined by CMV-IgG at 18 months and timed by earlier CMV-IgM or -DNA. Correlations were assessed using logistic regression.
In utero HIV infection was independently associated with congenital CMV infection (P=0.01), intrapartum HIV infection with congenital-plus-intrapartum/neonatal CMV infection (P=0.01), and overall HIV with overall CMV infection (P=0.001), as well as prematurity (P=0.004).
Congenital and acquired CMV infections are strong independent correlates of mother-to-child HIV transmission.
doi:10.1097/QAI.0b013e31822d0433
PMCID: PMC3237680  PMID: 21792064
14.  Resistance Patterns Selected by Nevirapine vs. Efavirenz in HIV-Infected Patients Failing First-Line Antiretroviral Treatment: A Bayesian Analysis 
PLoS ONE  2011;6(11):e27427.
Background
WHO recommends starting therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs), i.e. nevirapine or efavirenz, with lamivudine or emtricitabine, plus zidovudine or tenofovir. Few studies have compared resistance patterns induced by efavirenz and nevirapine in patients infected with the CRF01_AE Southeast Asian HIV-subtype. We compared patterns of NNRTI- and NRTI-associated mutations in Thai adults failing first-line nevirapine- and efavirenz -based combinations, using Bayesian statistics to optimize use of data.
Methods and Findings
In a treatment cohort of HIV-infected adults on NNRTI-based regimens, 119 experienced virologic failure (>500 copies/mL), with resistance mutations detected by consensus sequencing. Mutations were analyzed in relation to demographic, clinical, and laboratory variables at time of genotyping. The Geno2Pheno system was used to evaluate second-line drug options. Eighty-nine subjects were on nevirapine and 30 on efavirenz. The NRTI backbone consisted of lamivudine or emtricitabine plus either zidovudine (37), stavudine (65), or tenofovir (19). The K103N mutation was detected in 83% of patients on efavirenz vs. 28% on nevirapine, whereas Y181C was detected in 56% on nevirapine vs. 20% efavirenz. M184V was more common with nevirapine (87%) than efavirenz (63%). Nevirapine favored TAM-2 resistance pathways whereas efavirenz selected both TAM-2 and TAM-1 pathways. Emergence of TAM-2 mutations increased with the duration of virologic replication (OR 1.25–1.87 per month increment). In zidovudine-containing regimens, the overall risk of resistance across all drugs was lower with nevirapine than with efavirenz, whereas in tenofovir-containing regimen the opposite was true.
Conclusions
TAM-2 was the major NRTI resistance pathway for CRF01_AE, particularly with nevirapine; it appeared late after virological failure. In patients who failed, there appeared to be more second-line drug options when zidovudine was combined with nevirapine or tenofovir with efavirenz than with alternative combinations.
doi:10.1371/journal.pone.0027427
PMCID: PMC3223170  PMID: 22132100
15.  Hematological Safety of Perinatal Exposure to Zidovudine in Uninfected Infants Born to HIV Type 1-Infected Women in Thailand 
AIDS Research and Human Retroviruses  2010;26(10):1163-1166.
Abstract
The evolution of hematological parameters in HIV-1-exposed uninfected infants according to various durations of perinatal zidovudine exposure was studied. We used data prospectively collected among 1122 HIV-uninfected formula-fed infants born to HIV-infected mothers who participated in a clinical trial to prevent perinatal transmission in Thailand (PHPT-1). Infants were exposed to different durations of zidovudine both in utero and after birth. Hemoglobin level and leukocyte, absolute neutrophil, and lymphocyte counts were measured at birth and at 6 weeks of age. The association between hematological parameters at birth and the duration of zidovudine exposure in utero was studied using a linear regression model, and changes between birth and 6 weeks of age and the duration of postnatal zidovudine exposure using mixed effects models. At birth, the hemoglobin level was lower in newborns exposed to zidovudine for more than 7.5 weeks in utero (adjusted regression coefficient: −0.6 g/dl; 95% confidence interval: −1.1 to −0.1). Six weeks after birth, the hemoglobin level had decreased faster in infants administered zidovudine for more than 4 weeks (adjusted regression coefficient: −0.1 g/dl; 95% confidence interval: −0.2 to −0.1). The duration of perinatal zidovudine exposure was not associated with the evolution of leukocyte, neutrophil, and lymphocyte counts. Despite the differences in hemoglobin levels, grade 3 or 4 anemia did not significantly differ by maternal or infant zidovudine duration. The clinical impact appeared modest, but longer exposure may warrant close monitoring.
doi:10.1089/aid.2010.0034
PMCID: PMC2982712  PMID: 20854205
16.  Pharmacokinetics and virologic response of zidovudine/lopinavir/ritonavir initiated during the third trimester of pregnancy 
AIDS (London, England)  2010;24(14):2193-2200.
Objective
To evaluate the pharmacokinetics and HIV viral load (VL) response following initiation during the third trimester of pregnancy of zidovudine (ZDV) plus standard dose lopinavir boosted with ritonavir (LPV/r), twice daily, until delivery for the prevention of mother-to-child transmission of HIV (PMTCT).
Design
Prospective study nested within a multicenter, three arm, randomised, phase III PMTCT trial in Thailand (PHPT-5, ClinicalTrials.gov Identifier: NCT00409591).
Methods
Women randomized to receive 300 mg ZDV and 400/100 mg LPV/r twice daily from 28 weeks’ gestation, or as soon as possible thereafter, until delivery had intensive steady-state 12-hour blood sampling performed. LPV/r pharmacokinetic parameters were calculated using non-compartmental analysis. Rules were defined a priori for a LPV/r dose escalation based on the proportion of women with an LPV AUC < 52 mcg.hr/mL (10th percentile for LPV AUC in non-pregnant adults). HIV-1 RNA response was assessed during the third trimester.
Results
Thirty-eight women were evaluable; at entry median (range) gestational age was 29 weeks (28–36), weight 59.5 kg (45.0–91.6), CD4 cell count 442 cells/mm3 (260–1327) and HIV-1 RNA viral load 7,818 copies/mL (<40–402,015). Geometric mean (90% confidence interval) LPV AUC, Cmax and Cmin were 64.6 mcg.hr/mL (59.7–69.8), 8.1 mcg/mL, (7.5–8.7) and 2.7 mcg/ml (2.4–3.0), respectively. 31 of 38 (81%) women had an LPV AUC above the AUC target. All women had a HIV-1 viral load less than 400 copies/mL at the time of delivery.
Conclusion
A short course of ZDV plus standard dose LPV/r initiated during the 3rd trimester of pregnancy achieved adequate LPV exposure and virologic response.
doi:10.1097/QAD.0b013e32833ce57d
PMCID: PMC3070207  PMID: 20625263
lopinavir; pregnancy; pharmacokinetics; viral load; prevention of mother-to-child transmission of HIV
17.  Human immunodeficiency virus–hepatitis C virus co-infection in pregnant women and perinatal transmission to infants in Thailand 
Summary
Objectives
The objectives of this study were to assess the prevalence and factors associated with hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected and -uninfected Thai pregnant women and the rate of HCV transmission to their infants.
Patients and methods
Study subjects included 1435 HIV-infected pregnant women and their infants, enrolled in a perinatal HIV prevention trial, and a control group of 448 HIV-uninfected pregnant women. Women were screened for HCV antibodies with an enzyme immunoassay. Positive results were confirmed by recombinant immunoblot and HCV RNA quantification. Infants were tested for HCV antibodies at 18 months or for HCV RNA at between 6 weeks and 6 months.
Results
Of the HIV-infected women, 2.9% were HCV-infected compared to 0.5% of HIV-uninfected women (p = 0.001). Only history of intravenous drug use was associated with HCV infection in HIV-infected women. Ten percent of infants born to co-infected mothers acquired HCV. The risk of transmission was associated with a high maternal HCV RNA (p = 0.012), but not with HIV-1 load or CD4 count.
Conclusions
Acquisition of HCV through intravenous drug use partially explains the higher rate of HCV infection in HIV-infected Thai women than in HIV-uninfected controls. Perinatal transmission occurred in 10% of infants of HIV–HCV-co-infected mothers and was associated with high maternal HCV RNA.
doi:10.1016/j.ijid.2009.09.002
PMCID: PMC2886172  PMID: 20047847
HIV; HCV; Risk factors; Perinatal transmission; Intravenous drug use; Thailand
18.  Early HIV-1 diagnosis using in-house real time PCR amplification on dried blood spots for infants in remote and resource limited settings 
Background
In resource-limited settings, most perinatally HIV-1-infected infants do not receive timely antiretroviral therapy because early HIV-1 diagnosis is not available or affordable.
Objective
To assess the performance of a low cost in-house real-time PCR assay to detect HIV-1 DNA in infant dried blood spots (DBS).
Methods
1319 DBS collected throughout Thailand from non-breastfed infants born to HIV-1-infected mothers were shipped at room temperature to a central laboratory. In-house real-time DNA-PCR results were compared to Roche Amplicor® HIV-1 DNA test (Version 1.5) results. In addition, we verified the Roche test performance on DBS sampled from 1218 other infants using as reference HIV serology result at 18 months of age.
Results
Real-time DNA-PCR and Roche DNA-PCR results were 100% concordant. Compared to HIV-serology results, the Roche test sensitivity was 98.6% (95% CI: 92.6 to 100.0%) and its specificity at 4 months of age was 99.7% (95% CI: 99.2 to 99.9%).
Conclusions
In-house real-time PCR performed as well as the Roche test in detecting HIV-1 DNA on DBS in Thailand. Combined use of DBS and real-time PCR assays is a reliable and affordable tool to expand access to early HIV-1 diagnosis in remote and resource-limited settings, enabling timely treatment for HIV-1-infected infants.
doi:10.1097/QAI.0b013e31818e2531
PMCID: PMC3111749  PMID: 18989220
HIV-1 real-time DNA-PCR; Dried Blood Spots; early diagnosis; infant; access to treatment; remote and resource limited-settings
19.  Detection of HIV-1 DNA resistance mutations by a sensitive assay at initiation of antiretroviral therapy is associated with virologic failure 
Background
Antiretroviral therapy (ART) has become more available throughout the developing world during the past five years. The World Health Organization recommends nonnucleoside reverse transcriptase inhibitor-based regimens as initial ART. However, their efficacy may be compromised by resistance mutations selected by single-dose nevirapine (sdNVP) used to prevent mother-to-child-transmission of HIV-1 (PMTCT). There is no simple and efficient method to detect such mutations at initiation of ART.
Methods
181 women participating in a PMTCT clinical trial who started NVP-ART after they had received sdNVP or placebo were tested for nevirapine-resistance point-mutations (K103N, Y181C, and G190A) using 100 copies of HIV-1 DNA with a sensitive oligonucleotide ligation assay (OLA) able to detect mutants at low concentrations (≥5% of the viral population). Virologic failure was defined as plasma HIV-1 RNA confirmed >50 copies/mL between 6–18 months of NVP-ART.
Results
At initiation of NVP-ART, resistance mutations were identified in 26% of 148 participants given sdNVP (K103N-13%, Y181C-5%, G190A-19%; ≥2 mutations-10%) at a median 9.3 months after sdNVP. The risk of virologic failure was .62 (95% confidence interval (CI), 0.46–0.77) in women with ≥1 resistance mutation, compared to 0.25 (95% CI, 0.17–0.35) in those without detectable resistance mutations (P<.0001). Failure was independently associated with resistance, an interval of <6 months between sdNVP and NVP-ART initiation, and a viral load above the median at NVP-ART initiation.
Conclusions
Access to simple and inexpensive assays to detect low-concentrations of NVP-resistant HIV-1 DNA prior to the initiation of ART could help improve the outcome of first-line antiretroviral therapy.
doi:10.1086/652148
PMCID: PMC2856716  PMID: 20377404
HIV-1; resistance mutations; nevirapine; HAART; oligonucleotide ligation assay; developing countries
20.  Efficacy and safety of one-month postpartum zidovudine and didanosine to prevent HIV-resistance mutations following intrapartum single-dose nevirapine 
Background
Intrapartum single-dose-nevirapine along with third trimester maternal and infant zidovudine are essential components of programs to prevent mother-to-child HIV transmission in resource-limited settings. The persistence of nevirapine in the plasma for three weeks postpartum risks selection of resistance mutations to non-nucleoside reverse transcriptase inhibitors (NNRTI). We hypothesized that a one-month zidovudine-plus-didanosine course initiated at the same time as single-dose nevirapine would prevent the selection of nevirapine resistance mutations.
Methods
PHPT-4 HIV-infected pregnant women with CD4 counts above 250 cells/mm3 received antepartum zidovudine from the third trimester until delivery, single-dose nevirapine during labor and one-month zidovudine-plus-didanosine postpartum. These women were matched on baseline viral load (VL), CD4 count and duration of antepartum zidovudine to women who received single-dose nevirapine in the PHPT-2 trial (controls). Consensus sequencing and the more sensitive oligonucleotide ligation assay (OLA) were performed on samples drawn at 7–10, 37–45 and 120 days postpartum (if VL>500 copies/mL) to detect K103N/Y181C/G190A mutations.
Results
The 222 PHPT-4 subjects did not differ from their matched controls in baseline characteristics except for age. Combined groups median CD4 count was 421 cells/mm3 [IQR: 322–549], VL 3.45 log10 copies/mL [2.79–4.00] and ZDV prophylaxis 10.4 weeks [9.1–11.4]. Using consensus sequencing, major NNRTI resistance mutations were detected postpartum in 0% of PHPT-4 subjects versus 10.4% of PHPT-2 controls. OLA detected resistance in 1.8% of PHPT-4 subjects versus 18.9% controls. Major NNRTI resistance mutations were detected by either method in 1.8% of PHPT-4 subjects versus 20.7% in controls (p<10−10).
Conclusions
One-month postpartum zidovudine-plus-didanosine prevented the selection of vast majority NNRTI resistance mutations.
doi:10.1086/650745
PMCID: PMC2922986  PMID: 20158398
Nevirapine resistance mutations; zidovudine-plus-didanosine; HIV/AIDS; maternal-fetal transmission; public health
21.  Influence of CYP2B6 polymorphisms on the persistence of plasma nevirapine concentrations following a single intra-partum dose for the prevention of mother to child transmission in HIV-infected Thai women 
Objectives
To investigate the association of single nucleotide polymorphisms (SNPs) with nevirapine concentrations following intra-partum single-dose nevirapine.
Methods
Plasma and DNA samples were obtained from 330 HIV-infected Thai women who received intra-partum single-dose nevirapine in the PHPT-2 clinical trial to prevent perinatal HIV transmission. Nine SNPs within CYP2B6, CYP3A4 and ABCB1 were genotyped by real-time PCR. Nevirapine plasma concentrations were determined by HPLC and used in a population pharmacokinetic analysis.
Results
Higher nevirapine exposure was observed in women carrying the CYP2B6 516G>T polymorphism, but this did not reach statistical significance (P = 0.054). The TGATC CYP2B6 haplotype (g.3003T, 516G, 785A, g.18492T and g.21563C) was associated with increased nevirapine clearance and lower exposure (P = 0.0029). The median time for nevirapine concentrations to reach 10 ng/mL post-partum (nevirapine IC50 for HIV-1) was 14 days [interquartile range (IQR, 14–18)] for TGATC homozygotes, 16 days (14–20) for TGATC heterozygotes and 18 days (14–20) for non-TGATC homozygotes (P = 0.020).
Conclusions
The CYP2B6 516G>T impact on nevirapine concentrations was less pronounced after intra-partum single-dose nevirapine than reported under steady-state conditions, perhaps due to lack of enzyme auto-induction at the time of dosing. Although the TGATC CYP2B6 haplotype may shorten the persistence of nevirapine post-partum, its practical implications for the prevention of HIV transmission or selection of resistance mutations are likely limited.
doi:10.1093/jac/dkp351
PMCID: PMC2775665  PMID: 19812066
pharmacogenetics; single nucleotide polymorphisms; SNPs
22.  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▿  
Journal of Clinical Microbiology  2010;48(5):1555-1561.
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.
doi:10.1128/JCM.02062-09
PMCID: PMC2863880  PMID: 20181911
23.  Immunochromatographic Strip Test for Rapid Detection of Nevirapine in Plasma Samples from Human Immunodeficiency Virus-Infected Patients▿  
We report a novel one-step immunochromatographic strip test for the rapid, qualitative detection of nevirapine in plasma samples from human immunodeficiency virus-infected patients. The sensitivity was 100% (95% confidence interval [95% CI], 97.8 to 100%), and the specificity was 99.5% (95% CI, 97.2 to 99.9%). The limit of detection was 25 ng/ml. Immunochromatographic strip tests are simple, rapid, and cheap assays that could greatly facilitate drug level monitoring in resource-limited settings.
doi:10.1128/AAC.00445-07
PMCID: PMC2043209  PMID: 17606683
24.  Haematological Safety of Perinatal Zidovudine in Pregnant HIV-1–Infected Women in Thailand: Secondary Analysis of a Randomized Trial 
PLoS Clinical Trials  2007;2(4):e11.
Objectives:
To respond to the primary safety objective of the Perinatal HIV Prevention Trial 1 (PHPT-1) by studying the evolution of haematological parameters according to zidovudine exposure duration in HIV-1−infected pregnant women.
Design:
Multicenter, randomized, double-blind, controlled trial of different durations of zidovudine prophylaxis.
Setting:
27 hospitals in Thailand.
Participants:
1,436 HIV-infected pregnant women in PHPT-1.
Intervention:
Zidovudine prophylaxis initiation at 28 or 35 wk gestation.
Outcome measures:
Haemoglobin level, leucocytes, total lymphocyte counts, and absolute neutrophil counts were measured at 26, 32, and 35 wk and at delivery. The evolution of haematological parameters was estimated between 26 and 35 wk (zidovudine/placebo) and between 35 wk and delivery to compare a long versus short zidovudine exposure. For each parameter, linear mixed models were adjusted on baseline sociodemographic variables, HIV clinical stage, CD4 count, and viral load.
Results:
Between 26 and 35 wk, haemoglobin, leucocytes, and absolute neutrophil counts decreased in zidovudine-exposed compared to unexposed women (mean difference [95% CI] −0.4 [−0.5 to −0.3], −423 [−703 to −142], −485 [−757 to −213], respectively). However, between 35 wk and delivery, the haematological parameters increased faster in women exposed to long rather than short durations of zidovudine (0.1 [0.0 to 0.1]; 105 [18 to 191]; 147 [59 to 234], respectively). At delivery, the differences were not statistically significant, except for mean haemoglobin level, which remained slightly lower in the long zidovudine treatment group (difference: 0.2 g/dl). Zidovudine had no negative impact on the absolute lymphocyte counts.
Conclusion:
Zidovudine initiated at 28 wk gestation rather than 35 wk had a transient negative impact on the evolution of haematological parameters, which was largely reversed by delivery despite continuation of zidovudine. This result provides reassurance about the safety of early initiation of zidovudine prophylaxis during pregnancy to maximize prevention of perinatal HIV.
Editorial Commentary
Background: Pregnant women who are infected with HIV are at high risk of passing on the virus to their unborn baby during pregnancy, labour, and breastfeeding. Around 15%–30% of babies born to HIV-positive women will themselves become infected, if the woman avoids breast-feeding but does not use any other means of preventing the virus from being passed on. However, if a drug, zidovudine (AZT), is given during pregnancy the chance of HIV being passed on to a baby drops from around 23% to around 8%. In some settings it may not be realistic to give the standard course of zidovudine, from 28 weeks of pregnancy, because of its cost and complexity. A number of trials have therefore looked at whether standard-course and short-course zidovudine are equivalent at reducing the risk of passing on HIV from mother to baby. One trial, the Perinatal HIV Prevention Trial-1 (PHPT-1) found that the short treatment course was substantially less effective at preventing HIV from being passed on from mother to baby. Current international guidance therefore recommends starting zidovudine at 28 weeks of pregnancy. However, zidovudine does have several side effects, including anemia; it can also cause a drop in the levels of certain types of white blood cell, and is thought to be toxic to bone marrow. The researchers who had carried out the PHPT-1 trial therefore wanted to do a subsequent analysis of data from that trial to find out whether there were any differences in these safety outcomes between standard and short course zidovudine.
What the trial shows: In total 1,436 women were recruited into the trial and assigned to receive either zidovudine from 28 weeks of pregnancy until delivery (standard course; 769 women), or from 35 weeks to delivery (short course; 667). Blood tests were performed at 26, 32, and 35 weeks of pregnancy and then at delivery, and the main outcomes assessed in this secondary analysis were the hemoglobin levels (to check for anemia), and levels of white blood cells, including the levels of two particular types (neutrophils and lymphocytes). The researchers found that standard-course zidovudine resulted in a drop at 35 weeks in the levels of hemoglobin and white blood cells, relative to short-course zidovudine. However, by the time of delivery these levels had recovered and no significant differences could be observed between the two arms of the trial. Women receiving standard-course zidovudine were more likely to experience severe anemia, which although a rare event in both arms of the trial, could have serious outcomes.
Strengths and limitations: The original trial from which these data were collected was a relatively large, randomized study and in which there was a low rate of loss to follow up. Although no formal sample size calculation was performed for the analyses presented here, the study probably had sufficient power to detect small differences in the outcomes assessed. A key limitation of this study is that the analyses presented here are a secondary exploration of data from the PHPT-1 trial and should therefore be seen as hypotheses to test in further studies, rather than as definitive conclusions.
Contribution to the evidence: The analyses presented here add to the findings of the parent trial, PHPT-1, by providing additional data about the toxicity of zidovudine. Other trials have not clearly established whether there are differences between short- and standard-course zidovudine in terms of their toxicity. The findings support current guidelines recommending standard-course zidovudine therapy for HIV-positive pregnant women. It is also crucial that efforts are made to ensure women worldwide can get access to facilities for monitoring the status of their HIV infection, and then receive highly active antiretroviral therapy when it is needed.
doi:10.1371/journal.pctr.0020011
PMCID: PMC1863515  PMID: 17476315

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