Non-nucleoside reverse transcriptase inhibitor outcomes among combination antiretroviral therapy-treated adults in Botswana.

Background: National initiatives offering non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination antiretroviral therapy (cART) have expanded in sub-Saharan Africa. The Tshepo study is the first clinical trial evaluating the long-term efficacy and tolerability of efavirenz versus nevirapine-based cART among adults in Botswana.

Methods: A 3-year randomized study (n = 650) using a 3 x 2 x 2 factorial design comparing efficacy and tolerability among: (i) zidovudine/lamivudine versus zidovudine/didanosine versus stavudine/lamivudine; (ii) efavirenz versus nevirapine; and (iii) community-based supervision versus standard adherence strategies.

AIDS denialism and public health practice.

In this paper, we respond to AIDS denialist arguments that HIV does not cause AIDS, that antiretroviral drugs are not useful, and that there is no evidence of large-scale deaths from AIDS, and discuss the key implications of the relationship between AIDS denialism and public health practice. We provide a brief history of how the cause of AIDS was investigated, of how HIV fulfills Koch's postulates and Sir Bradford Hil's criteria for causation, and of the inconsistencies in alternatives offered by denialists. We highlight clinical trials as the standard for assessing efficacy of drugs, rather than anecdotal cases or discussions of mechanism of action, and show the unanimous data demonstrating antiretroviral drug efficacy.

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.

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.

Perceptions of couple HIV counseling and testing in Botswana: a stakeholder analysis.

Objective: To explore stakeholder's perceptions of Couples HIV Counseling and Testing (CHCT) as opposed to individual testing and potential couples' preferences for CHCT promotion and service provision.

Methods: Study was conducted as formative research for a phase III clinical trial of Herpes (HSV-2) suppression to prevent HIV transmission among HIV discordant couples. We used non-probability purposive sampling and snowballing techniques to identify study participants.

Response to zidovudine/didanosine-containing combination antiretroviral therapy among HIV-1 subtype C-infected adults in Botswana: two-year outcomes from a randomized clinical trial.

Background: Numerous national antiretroviral (ARV) treatment initiatives offering protease inhibitor-sparing combination antiretroviral therapy (cART) have recently commenced in southern Africa, the first of which began in Botswana in January 2002. Evaluation of the efficacy and tolerability of various protease inhibitor-sparing cART regimens requires intensive study in the region, as does investigation of the development of drug resistance and the optimal means of sustaining adherence. The "Tshepo" Study is the first large-scale, randomized, clinical trial that addresses these important issues among HIV-1 subtype C-infected ARV treatment-naive adults in southern Africa.

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.

Reduced viral replication capacity of human immunodeficiency virus type 1 subtype C caused by cytotoxic-T-lymphocyte escape mutations in HLA-B57 epitopes of capsid protein.

Cytotoxic-T-lymphocyte (CTL) escape mutations in human immunodeficiency viruses encode amino acid substitutions in positions that disrupt CTL targeting, thereby increasing virus survival and conferring a relative fitness benefit. However, it is now clear that CTL escape mutations can also confer a fitness cost, and there is increasing evidence to suggest that in some cases, e.g.

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.

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.

Higher-than-expected rates of lactic acidosis among highly active antiretroviral therapy-treated women in Botswana: preliminary results from a large randomized clinical trial.

Background: The ability of nucleoside reverse transcriptase inhibitors (NRTIs) to inhibit human mitochondrial polymerase-gamma results in impaired synthesis of mitochondrial enzymes that generate adenosine triphosphate (ATP) by oxidative phosphorylation. This has been associated with several long-term mitochondrial toxicities, which include lactic acidosis and pancreatitis, peripheral neuropathy, and lipoatrophy.

Methods: Enrolled highly active antiretroviral therapy (HAART)-treated adults have completed nearly 2 years of follow-up as part of the ongoing randomized clinical trial Adult Antiretroviral Treatment and Drug Resistance (Tshepo) study.

The complexity of circulating HIV type 1 strains in Oyo state, Nigeria.

Multiple HIV-1 subtypes and circulating recombinant forms (CRFs) are known to circulate in West Africa. We undertook a survey of HIVs in Oyo state, in southwestern Nigeria. We analyzed 71 samples from Ibadan, the capital city, and 33 samples from Saki, 100 miles west of Ibadan.

Infection of hematopoietic progenitor cells by HIV-1 subtype C, and its association with anemia in southern Africa.

Reports from southern Africa, an area in which human immunodeficiency virus type 1 (HIV-1) infection is caused almost exclusively by subtype C (HIV-1C), have shown increased rates of anemia in HIV-infected populations compared with similar acquired immunodeficiency syndrome (AIDS) patients in the United States, an area predominantly infected with subtype B (HIV-1B). Recent findings by our group demonstrated a direct association between HIV-1 infection and hematopoietic progenitor cell health in Botswana. Therefore, using a single-colony infection assay and quantitative proviral analysis, we examined whether HIV-1C could infect hematopoietic progenitor cells (HPCs) and whether this phenotype was associated with the higher rates of anemia found in southern Africa.

A seronegative case of HIV-1 subtype C infection in Botswana.

We report the first case, to our knowledge, of antibody-negative human immunodeficiency virus type 1 (HIV-1) subtype C infection, which was identified during screening for acute HIV-1 infection in Botswana. Results of tests for HIV-1 antibodies were consistently negative, including rapid and regular enzyme-linked immunosorbent assay and Western blot. The nonrecombinant HIV-1 subtype C infection was confirmed by viral genotyping within the gag, pol, and env genes.

Pregnancy rates and birth outcomes among women on efavirenz-containing highly active antiretroviral therapy in Botswana.

Background: Millions of HIV-infected women in developing countries are in need of safe and highly effective antiretroviral therapy. Pregnancy rates are usually high in developing countries, and efavirenz (EFV) use in women of childbearing age is of concern because of its potential teratogenicity.

Methods: As part of a prospective study comparing 6 initial highly active antiretroviral therapy (HAART) regimens, 3 of which contained EFV, pregnancy and birth outcomes were evaluated among female participants enrolled in a randomized clinical trial in Botswana.

Serological evidence of HIV-associated infection among HIV-1-infected adults in Botswana.

In industrialized countries, it is recommended that adults with human immunodeficiency virus type 1 (HIV-1) infection undergo baseline screening for pathogens that might cause latent or active infections, such as syphilis, hepatitis B, hepatitis C, infection due to Toxoplasma gondii, and cytomegalovirus infection. A paucity of data exist from sub-Saharan Africa describing the prevalence of these pathogens. We report data for HIV-1-infected adults referred for initiation of highly active antiretroviral therapy in Botswana.

High prevalence of the K65R mutation in human immunodeficiency virus type 1 subtype C isolates from infected patients in Botswana treated with didanosine-based regimens.

We analyzed the reverse transcriptase genotypes of human immunodeficiency virus type 1 subtype C viruses isolated from 23 patients in Botswana treated with didanosine-based regimens. The K65R mutation was selected either alone or together with the Q151M, S68G, or F116Y substitution in viruses from seven such individuals. The results of in vitro passage experiments were consistent with an apparent increased propensity of subtype C viruses to develop the K65R substitution.

HIV/AIDS, income loss and economic survival in Botswana.

In countries facing severe HIV/AIDS epidemics, the overwhelming majority of those who are infected and affected by HIV are already living in poverty. Further income loss can threaten the ability to meet basic needs such as food, education and access to healthcare. Due to this, understanding the impact of HIV infection and caregiving on household income is essential to improving the health and welfare of HIV-affected individuals and families.

Impact of human immunodeficiency virus type 1 subtype C on drug resistance mutations in patients from Botswana failing a nelfinavir-containing regimen.

Among 16 human immunodeficiency virus-infected (subtype C) Batswana patients who failed nelfinavir (NFV)-containing regimens, the most prevalent mutation observed was D30N (54%), followed by L90M (31%). L89I, K20T/I, and E35D polymorphic changes were also identified. These findings suggest that subtype C viruses in Botswana may develop resistance to NFV via subtype-specific pathways.

Risk of HIV-1 transmission by breastfeeding among mothers infected with recombinant and non-recombinant HIV-1 genotypes.

Background: Viral genotype and intersubtype recombination may influence the rate and/or timing of mother-to-child HIV-1 transmission.

Methods: We determined the HIV-1 subtype of the C2-C5 env and 5'LTR regions from milk and blood samples of 61 Tanzanian mothers who transmitted the virus through breastfeeding and their HIV-1 positive non-transmitting controls. Cases and controls were matched on infant's age at sample collection.

Hybrid data capture for monitoring patients on highly active antiretroviral therapy (HAART) in urban Botswana.

Individual patient care and programme evaluation are pivotal for the success of antiretroviral treatment programmes in resource-limited countries. While computer-aided documentation and data storage are indispensable for any large programme, several important issues need to be addressed including which data are to be collected, who collects it and how it is entered into an electronic database. We describe a patient-monitoring approach, which uses patient encounter forms (in hybrid paper + electronic format) based on optical character recognition, piloted at Princess Marina Hospital in Gaborone, Botswana's first public highly active antiretroviral therapy (HAART) outpatient clinic.

HIV-1 subtype C in vitro growth and coreceptor utilization.

Human immunodeficiency virus type 1 subtype C (HIV-1C) accounts for about 50% of all HIV infections in the pandemic and is the predominant subtype in the heavily burdened region of southern Africa. HIV-1C possesses unique genetic and phenotypic features that might be associated with biological differences compared to other subtypes. Here, we generated virus isolates from individuals at different stages of HIV-1C infection and investigated the chemokine receptor repertoire that the derived HIV-1C isolates may utilize for entry.

Transmission of cell-free and cell-associated HIV-1 through breast-feeding.

Background: Transmission through breast-feeding is an important cause of infant HIV-1 infections in developing countries; however, its mechanism remains largely unknown. We have explored the association between cell-free virus (CFV) and cell-associated virus (CAV) levels in breast milk (BM), as reflected by viral RNA and proviral DNA, respectively, and the risk of infant HIV-1 infection after 6 weeks postpartum.

Methods: Sixty-one HIV-positive mothers who transmitted HIV-1 by BM were matched to 61 HIV-positive nontransmitting mothers based on their infant's age at sample collection.

Initial response to highly active antiretroviral therapy in HIV-1C-infected adults in a public sector treatment program in Botswana.

Objective: To describe the response to highly active antiretroviral treatment (HAART) in a public sector pilot antiretroviral (ARV) treatment program in Botswana.

Methods: The response to HAART is described in adult HIV-infected ARV-naive patients initiating treatment from April 2001 to January 2002 at Princess Marina Hospital in Gaborone, Botswana. Patients had medical and laboratory evaluations before initiating ARV treatment and were followed longitudinally.