Ndwapi

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. Data analysis was conducted on available longitudinal data up to 1st April 2007. Results: Six hundred thirty-three severely immunodeficient patients with a median CD4+ cell count of 67 cells/μl were initiated on non-nucleoside reverse transcriptase inhibitor-based combination ART and followed for a median of 41.9 months. The median CD4+ cell count increases were 169, 302, and 337 cells/μl at 1, 3, and 5 years, respectively. The percentages of patients with a viral load of less than 400 copies/ml at 1, 3, and 5 years were 91.3, 90.1, and 98.3%, respectively. Seventy-five percent of patients did not miss a single, or missed only one, monthly ART pickup per year with a mean pickup rate of 92.5%. The Kaplan–Meier survival estimates [95% confidence interval (CI)] at 1, 3, and 5 years were 82.7% (81.2 and 84.3%), 79.3% (77.6 and 81.0%), and 79.0% (77.3 and 80.7%), respectively. At 6 months, the risk of treatment modification for anemia was 6.94% (5.9 and 8.0%) for cutaneous hypersensitivity reactions, 1.3% (0.8 and 1.7%), and 1.1% (0.7 and 1.6%) for hepatotoxicity. Conclusion: This initial group of adults on ART in Botswana had excellent sustained immunologic, virologic, and clinical outcomes for up to 5 years of follow-up with low mortality among those surviving into the second year of ART.

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. For analysis, data were collected from charts and patient management records. Results:One hundred fifty-three ARV-naive patients initiated HAART. Most received didanosine plus stavudine (ddI + d4T) with efavirenz or nevirapine. The mean CD4+ cell count increase was 149 cells/mm3 at 24 weeks and 204 cells/mm3 at 48 weeks. The percentage of patients with an HIV-1 RNA level ≤400 copies/mL was 87.0% at 24 weeks and 78.8% at 48 weeks. The Kaplan-Meier 1-year survival estimate was 84.7% (79.0%, 90.8%), with a 3.2-fold increased risk (P = 0.004) of mortality among patients with a CD4+ cell count <50 cells/mm3. The 1-year Kaplan-Meier estimate of toxicity-related drug switches was 32.2% (20.3%, 40.4%). The most common toxicity was peripheral neuropathy, occurring more frequently in patients with a preexisting diagnosis of peripheral neuropathy and among those placed on ddI + d4T-containing regimens. Conclusions:An excellent response to HAART was observed among HIV-1C-infected patients, paralleling those seen elsewhere. Despite excellent responses, high rates of toxicity were observed for ddI + d4T-containing regimens.

Overestimates of survival after HAART: implications for global scale-up efforts.

Background Monitoring the effectiveness of global antiretroviral therapy scale-up efforts in resource-limited settings is a global health priority, but is complicated by high rates of losses to follow-up after treatment initiation. Determining definitive outcomes of these lost patients, and the effects of losses to follow-up on estimates of survival and risk factors for death after HAART, are key to monitoring the effectiveness of global HAART scale-up efforts. Methodology/Principal Findings A cohort study comparing clinical outcomes and risk factors for death after HAART initiation as reported before and after tracing of patients lost to follow-up was conducted in Botswanas National Antiretroviral Therapy Program. 410 HIV-infected adults consecutively presenting for HAART were evaluated. The main outcome measures were death or loss to follow-up within the first year after HAART initiation. Of 68 patients initially categorized as lost, over half (58.8%) were confirmed dead after tracing. Patient tracing resulted in reporting of significantly lower survival rates when death was used as the outcome and losses to follow-up were censored [1-year Kaplan Meier survival estimate 0.92 (95% confidence interval, 0.88–0.94 before tracing and 0.83 (95% confidence interval, 0.79–0.86) after tracing, log rank P<0.001]. In addition, a significantly increased risk of death after HAART among men [adjusted hazard ratio 1.74 (95% confidence interval, 1.05–2.87)] would have been missed had patients not been traced [adjusted hazard ratio 1.41 (95% confidence interval, 0.65–3.05)]. Conclusions/Significance Due to high rates of death among patients lost to follow-up after HAART, survival rates may be inaccurate and important risk factors for death may be missed if patients are not actively traced. Patient tracing and uniform reporting of outcomes after HAART are needed to enable accurate monitoring of global HAART scale-up efforts.

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

ABSTRACT 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.

Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy.

Objective:To derive and internally validate a clinical prediction rule for virologic response based on CD4 cell count increase after initiation of HAART in a resource-limited setting. Design and methods:A retrospective cohort study at two HIV care clinics in Gaborone, Botswana. The participants were previously treatment-naive HIV-1-infected individuals initiating HAART. The main outcome measure was a plasma HIV-1 RNA level (viral load) ≤ 400 copies/ml (i.e. undetectable) 6 months after initiating HAART. Results:The ability of CD4 cell count increase to predict an undetectable viral load was significantly better in those with baseline CD4 cell counts ≤ 100 cells/μl [area under the ROC curve (AUC), 0.78; 95% confidence interval (CI), 0.67–0.89; versus AUC, 0.60; 95% CI, 0.48–0.71; P = 0.018]. The sensitivity, specificity, and positive and negative predictive values of a CD4 cell count increase of ≥ 50 cells/μl for an undetectable viral load in those with baseline CD4 cell counts ≤ 100 cells/μl were 93.1, 61.3, 92.5 and 63.3%, respectively. Alternatively, these values were 47.8, 87.1, 95.0 and 24.5%, respectively, if a increase in CD4 cell count of ≥ 150 cells/μl was used. Conclusions:CD4 cell count increase after initiating HAART has only moderate discriminative ability in identifying patients with an undetectable viral load, and the predictive ability is lower in patients with lower baseline CD4 cell counts. Although HIV treatment programs in resource-constrained settings could consider the use of CD4 cell count increases to triage viral load testing, more accurate approaches to monitoring virologic failure are urgently needed.

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-γ 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. All patients were intensively screened for the presence of ARV-related toxicities. Results: Six hundred fifty adults (69% female) were initiated on NRTI-based HAART. Overall, 2.0% of patients developed moderate to severe symptomatic hyperlactatemia, with 7 (1.0%), all female, diagnosed with lactic acidosis. Female gender (P = 0.008) and being overweight, namely having a body mass index (BMI) of greater than 25 (P = 0.001), were predictive for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis. Older age (age >40 years) showed a statistical trend (P = 0.053) as a predictor for the development of toxicity, whereas exposure to d4T and/or ddI for 6 or more months was not predictive (P = 0.102). Those diagnosed with lactic acidosis had a mean BMI of 32.38 (interquartile range [IQR] = 29.4 to 35) at the time of toxicity and had been receiving HAART for a mean of 12.1 months (IQR = 7 to 20.8). Four of the 7 (57%) died of lactic acidosis and/or hemorrhagic pancreatitis; these 4 patients also had a comorbid diagnosis of severe clinical pancreatitis with grade 3/4 lipase elevations and abdominal symptoms at the time of their demise. Conclusions: Rates of lactic acidosis appear to be higher in southern Africa when compared with rates previously described elsewhere. Risk factors for the development of moderate to severe symptomatic hyperlactatemia or lactic acidosis appear to be multifactorial but include female gender and having a BMI of greater than 25. Additional studies are ongoing to evaluate for other possible risk factors, such as host genetic differences.

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. Methods:The Tshepo Study is a completed, open-labeled, randomized study that enrolled 650 ARV-naive adults between December 2002 and 2004. The study is a 3 × 2 × 2 factorial design comparing the efficacy and tolerability among factors: (1) 3 combinations of nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine (ZDV) + lamivudine (3TC), ZDV + didanosine (ddI), and stavudine (d4T) + 3TC; (2) 2 different nonnucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine and efavirenz; and (3) 2 different adherence strategies: the current national “standard of care” versus an “intensified adherence strategy” incorporating a “community-based directly observed therapy.” Study patients were stratified into 2 balanced CD4+ T-cell count groups: less than 201 versus 201-350 cells per cubic millimeter with viral load greater than 55,000 copies per milliliter. Following Data Safety Monitoring Board recommendations in April 2006, ZDV/ddI-containing arms were discontinued due to inferiority in primary end point, namely, virologic failure with resistance. We report both overall data and pooled data from patients receiving ZDV/ddI- versus ZDV/3TC- and d4T/3TC-containing cART through April 1, 2006. Results:Four hundred fifty-one females (69.4%) and 199 males with a median age of 33.3 years were enrolled into the study. The median follow-up as of April 1, 2006, was 104 weeks, and loss to follow-up rate at 2 years was 4.1%. The median baseline CD4+ T-cell count was 199 cells per cubic millimeter [interquartile ratio (IQR) 136-252], and the median plasma HIV-1 RNA level was 193,500 copies per milliliter (IQR 69-250, 472-500). The proportion of participants with virologic failure and genotypic resistance mutations was 11% in those receiving ZDV/ddI-based cART versus 2% in those receiving either ZDV/3TC- or d4T/3TC-based cART (P = 0.002). The median CD4+ T-cell count increase at 1 year was 137 cells per cubic millimeter (IQR 74-223) and 199 cells per cubic millimeter (IQR 112-322) at 2 years with significantly lower gain in the ZDV/ddI arm. At 1 and 2 years, respectively, 92.0% and 88.8% of patients had an undetectable plasma HIV-1 RNA level (≤400 copies/mL). Kaplan-Meier survival estimates at 1 and 2 years were 96.6% and 95.4%. One hundred twenty patients (18.2%) had treatment-modifying toxicities, of which the most common were lipodystrophy, anemia, neutropenia, and Stevens-Johnson syndrome. There was a trend toward difference in time to treatment-modifying toxicity by pooled dual-NRTI combination and no difference in death rates. Conclusions:The preliminary study results show overall excellent efficacy and tolerability of NNRTI-based cART among HIV-1 subtype C-infected adults. ZDV/ddI-containing cART, however, is inferior to the dual NRTIs d4T/3TC or ZDV/3TC when used with an NNRTI for first-line cART.

Establishment of a Public Antiretroviral Treatment Clinic for Adults in Urban Botswana: Lessons Learned

Countries in sub-Saharan Africa are under significant pressure to open large-scale, public antiretroviral treatment clinics. Many lessons have been learned in Botswana, where the first public antiretroviral treatment clinic in Africa was established. The availability of core, well-trained medical staff will be the primary factor that limits a rapid scale-up of antiretroviral treatment programs.

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.

Impact of Human Immunodeficiency Virus Type 1 Subtype C on Drug Resistance Mutations in Patients from Botswana Failing a Nelfinavir-Containing Regimen

ABSTRACT 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.