HIV-1 Subtype C Phylodynamics in the Global Epidemic.

The diversity of HIV-1 and its propensity to generate escape mutants present fundamental challenges to control efforts, including HIV vaccine design. Intra-host diversification of HIV is determined by immune responses elicited by an HIV-infected individual over the course of the infection. Complex and dynamic patterns of transmission of HIV lead to an even more complex population viral diversity over time, thus presenting enormous challenges to vaccine development.

Temporal reduction of HIV type 1 viral load in breast milk by single-dose nevirapine during prevention of MTCT.

Short-course zidovudine (ZDV) with or without a single dose of nevirapine (sdNVP) is widely used to prevent mother-to-child HIV transmission (PMTCT). However, more data on viral load in breast milk following pMTCT regimens are needed. In a randomized PMTCT study in Botswana, in which half of the women received sdNVP in labor, stored samples from mothers assigned to breastfeed were analyzed for HIV-1 RNA in breast milk supernatant.

Early risk factors and developmental pathways to chronic high inhibition and social anxiety disorder in adolescence.

Objective: Evidence suggests that chronic high levels of behavioral inhibition are a precursor of social anxiety disorder. The authors sought to identify early risk factors for, and developmental pathways to, chronic high inhibition among school-age children and the association of chronic high inhibition with social anxiety disorder by adolescence.

Method: A community sample of 238 children was followed from birth to grade 9.

Timing constraints of in vivo gag mutations during primary HIV-1 subtype C infection.

Background: Aiming to answer the broad question "When does mutation occur?" this study examined the time of appearance, dominance, and completeness of in vivo Gag mutations in primary HIV-1 subtype C infection.

Methods: A primary HIV-1C infection cohort comprised of 8 acutely and 34 recently infected subjects were followed frequently up to 500 days post-seroconversion (p/s). Gag mutations were analyzed by employing single-genome amplification and direct sequencing.

Antiretroviral treatment initiation among HIV-infected pregnant women with low CD4(+) cell counts in Gaborone, Botswana.

Background: Botswana has the most comprehensive public program in Africa for providing antiretroviral therapy to treat HIV and prevent mother-to-child transmission (PMTCT). Botswana guidelines prioritize CD4(+) cell count testing during pregnancy and initiation of highly active antiretroviral treatment (HAART) for women who qualify for treatment. We analyzed rates of HIV testing, CD4 cell count testing, and HAART initiation during pregnancy.

Five-year follow up of genotypic resistance patterns in HIV-1 subtype C infected patients in Botswana after failure of thymidine analogue-based regimens.

Objective: Our objective was to establish genotypic resistance profiles among the 4% of Batswana patients who experienced virologic failure while being followed within Botswana's National Antiretroviral Treatment Program between 2002 and 2007.

Methods: At the beginning of the national program in 2002, almost all patients received stavudine (d4T), together with didanosine (ddI), as part of their first nucleoside reverse transcriptase inhibitor (NRTI)-based regimen (Group 1). In contrast, the standard of care for all patients subsequently enrolled (2002-2007) included zidovudine/lamivudine (ZDV/3TC) (Group 2).

Better control of early viral replication is associated with slower rate of elicited antiviral antibodies in the detuned enzyme immunoassay during primary HIV-1C infection.

Background: Estimation of HIV incidence rates is important for timing interventions, planning prevention studies, and monitoring the epidemic. This requires accurate estimation of the "recency period" (also known as the "window period") between seroconversion and achievement of specific detectable levels of anti-HIV antibody titers, such as the standardized optical density (SOD) in the early phase of HIV-1 infection.

Methods: To obtain a better understanding of interpatient variation of the recency period, prospective measurements of antiviral antibody titers in the early phase of HIV-1 subtype C infection were quantified by Vironostika-LS.

Quantitation of human immunodeficiency virus type 1 viral load in plasma using reverse transcriptase activity assay at a district hospital laboratory in Botswana: a decentralization pilot study.

Roche COBAS Amplicor monitor version 1.5 assay is considered gold standard for viral load monitoring in Botswana. Due to its demand for elaborate infrastructure, viral load testing has been confined to the national HIV reference laboratories.

Screening for childhood mental health problems: outcomes and early identification.

Background: Many childhood psychiatric problems are transient. Consequently, screening procedures to accurately identify children with problems unlikely to remit and thus, in need of intervention, are of major public health concern. This study aimed to develop a universal school-based screening procedure based on the answers to three questions: (1) What are the broad patterns of mental health problems from kindergarten to grade 5? (2) What are the grade 5 outcomes of these patterns? (3) How early in school can children likely to develop the most impairing patterns be identified accurately?

Methods: Mothers and teachers reported on a community sample (N = 328) of children's internalizing and externalizing symptoms in kindergarten and grades 1, 3, and 5.

Characteristics of HIV-1 discordant couples enrolled in a trial of HSV-2 suppression to reduce HIV-1 transmission: the partners study.

Background: The Partners HSV-2/HIV-1 Transmission Study (Partners Study) is a phase III, placebo-controlled trial of daily acyclovir for genital herpes (HSV-2) suppression among HIV-1/HSV-2 co-infected persons to reduce HIV-1 transmission to their HIV-1 susceptible partners, which requires recruitment of HIV-1 serodiscordant heterosexual couples. We describe the baseline characteristics of this cohort.

Methods: HIV-1 serodiscordant heterosexual couples, in which the HIV-1 infected partner was HSV-2 seropositive, had a CD4 count >or=250 cells/mcL and was not on antiretroviral therapy, were enrolled at 14 sites in East and Southern Africa.

Viral load and CD4+ T-cell dynamics in primary HIV-1 subtype C infection.

Background: Most knowledge of primary HIV-1 infection is based on subtype B studies, whereas the evolution of viral parameters in the early phase of HIV-1 subtype C infection is not well characterized.

Methods: The kinetics of viral RNA, proviral DNA, CD4+ T-cell count, and subsets of CD4+ T cells expressing CCR5 or CXCR4 were characterized in 8 acute and 62 recent subtype C infections over the first year postseroconversion.

Results: The viral RNA peak was 6.

Safety and efficacy of nevirapine- and efavirenz-based antiretroviral treatment in adults treated for TB-HIV co-infection in Botswana.

Background: The safety and efficacy of nevirapine (NVP) and efavirenz (EFV) based highly active antiretroviral treatment (ART) with concurrent anti-tuberculosis treatment in sub-Saharan Africa has not been well established.

Methods: We performed a retrospective study comparing human immunodeficiency virus (HIV) infected adults exposed and not exposed to tuberculosis (TB) treatment with similar baseline HIV-1 RNA levels who were started on ART as part of Botswana's ART Programme. ART regimens, HIV-1 RNA, CD4+ cell count, and liver function tests were reviewed for 12 months following ART initiation.

Replicative capacity differences of thymidine analog resistance mutations in subtype B and C human immunodeficiency virus type 1.

In order to understand the impact of zidovudine resistance and thymidine analog mutations (TAMs) on subtype C human immunodeficiency virus type 1, we created mutants in subtype C reverse transcriptase (RT). The subtype B RT was placed in a subtype C backbone to act as a control. Mutants and wild-type (WT) virus were competed in a head-to-head competition assay to determine how different clones grew in the same culture.

Estimating the lost benefits of antiretroviral drug use in South Africa.

South Africa is one of the countries most severely affected by HIV/AIDS. At the peak of the epidemic, the government, going against consensus scientific opinion, argued that HIV was not the cause of AIDS and that antiretroviral (ARV) drugs were not useful for patients and declined to accept freely donated nevirapine and grants from the Global Fund. Using modeling, we compared the number of persons who received ARVs for treatment and prevention of mother-to-child HIV transmission between 2000 and 2005 with an alternative of what was reasonably feasible in the country during that period.

Risk factors for early and late transmission of HIV via breast-feeding among infants born to HIV-infected women in a randomized clinical trial in Botswana.

Risk factors for mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) via breast-feeding were evaluated in a randomized trial. HIV-infected women and their infants received zidovudine as well as single-dose nevirapine or placebo. Infants were randomized to formula-feed (FF) or breast-feed (BF) in combination with zidovudine prophylaxis.

Five-year outcomes of initial patients treated in Botswana's National Antiretroviral Treatment Program.

Background: Antiretroviral treatment (ART) initiatives have now been established in many sub-Saharan African countries showing early benefits. To date, few results are available concerning long-term clinical outcomes in these treatment programs.

Methods: Response to ART is described in the first HIV-1C-infected adults enrolled in the Botswana Antiretroviral Treatment Program in 2002.

Evolution of proviral gp120 over the first year of HIV-1 subtype C infection.

The evolution of proviral gp120 during the first year after seroconversion in HIV-1 subtype C infection was addressed in a case series of eight subjects. Multiple viral variants were found in two out of eight cases. Slow rate of viral RNA decline and high early viral RNA set point were associated with a higher level of proviral diversity from 0 to 200 days after seroconversion.

Concurrent and longitudinal associations of basal and diurnal cortisol with mental health symptoms in early adolescence.

Recent biosocial theories postulate that both biological risk and the social context influence the development of mental health problems [Boyce and Ellis (2005) Development and Psychopathology, 17(2), 271-301]. Guided by this framework, we examined whether basal cortisol and its diurnal rhythm were associated with mental health symptoms in early adolescence. Because cross-sectional and longitudinal investigations sometimes reveal different cortisol-mental health associations, we examined the association both concurrently and longitudinally when children transition to middle school, a time which entails a major change in social context from single to multiple teachers, classrooms, and sets of classmates.

Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants.

Objective: To assess hematologic and hepatic toxicities associated with in utero and breastfeeding exposure to maternal highly active antiretroviral therapy (HAART) among infants in Botswana.

Design: A nested cohort study within a randomized clinical trial (the Mashi Study). Laboratory toxicities among infants born to women who initiated HAART before delivery were compared with toxicities among those born to women who received zidovudine and a single dose of nevirapine or placebo in labor.

Identification of primary HIV-1C infection in Botswana.

Methods for identification of primary HIV infections seem increasingly important to understand pathogenesis, and to prevent transmission, which is particularly efficient during acute infection. Most current algorithms for HIV testing are based on detection of HIV antibodies and are unable to identify early infections before seroconversion. The efficiency of prospective cohorts, which is a standard approach for identifying primary HIV-1 infection, depends on a variety of epidemiological and cultural factors including HIV incidence and stigma and, not surprisingly, varies significantly in different geographical areas.

Efficacy of antiretroviral drugs in reducing mother-to-child transmission of HIV in Africa: a meta-analysis of published clinical trials.

Antiretroviral drugs (ARVs) have been shown to be efficacious in decreasing mother-to-child transmission (MTCT) of HIV. A summary estimate of the efficacy of ARVs in reducing MTCT is important for modeling and policy decisions. However, no one has hitherto attempted to generate this summary estimate for Africa, the continent with the greatest HIV/AIDS burden.

How and why criteria defining moderators and mediators differ between the Baron & Kenny and MacArthur approaches.

Objective: In recognition of the increasingly important role of moderators and mediators in clinical research, clear definitions are sought of the two terms to avoid inconsistent, ambiguous, and possibly misleading results across clinical research studies.

Design: The criteria used to define moderators and mediators proposed by the Baron & Kenny approach, which have been long used in social/behavioral research, are directly compared to the criteria proposed by the recent MacArthur approach, which modified the Baron & Kenny criteria.

Results: After clarifying the differences in criteria between approaches, the rationale for the modifications is clarified and the implications for the design and interpretation of future studies considered.