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

Wester, C Williama,b,e; Thomas, Ann Muirc; Bussmann, Hermanna,b; Moyo, Sikhulileb; Makhema, Joseph Mb; Gaolathe, Tendanib,d; Novitsky, Vladimira,b; Essex, Maxa,b; deGruttola, Victorc; Marlink, Richard Ga,b

doi: 10.1097/01.aids.0000366080.91192.55

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 × 2 × 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. This paper focuses on comparison (ii).

Results: There was no significant difference by assigned NNRTI in time to virological failure with resistance (log-rank P = 0.14), nevirapine versus efavirenz [risk ratio (RR) 1.54, 95% CI 0.86–2.70]. Rates of virological failure with resistance were 9.6% nevirapine-treated (95% CI 6.8–13.5) versus 6.6% efavirenz-treated (95% CI 4.2–10.0) at 3 years. Women receiving nevirapine-based cART trended towards higher virological failure rates when compared with efavirenz-treated women, Holm-corrected (log-rank P = 0.072), nevirapine versus efavirenz (RR 2.22, 95% CI 0.94–5.00). A total of 139 patients had 176 treatment-modifying toxicities, with a shorter time to event in nevirapine-treated versus efavirenz-treated patients (RR 1.85, 1.20–2.86; log-rank P = 0.0002).

Conclusion: Tshepo-treated patients had excellent overall immunological and virological outcomes, and no significant differences were observed by randomized NNRTI comparison. Nevirapine-treated women trended towards higher virological failure with resistance compared with efavirenz-treated women. Nevirapine-treated adults had higher treatment modifying toxicity rates when compared with those receiving efavirenz. Nevirapine-based cART can continue to be offered to women in sub-Saharan Africa if patient education concerning toxicity is emphasized, routine safety monitoring chemistries are performed and the potential risk of efavirenz-related teratogenicity is considered.

Author Information

aBotswana–Harvard School of Public Health AIDS Initiative Partnership for HIV Research and Education (BHP), Gaborone, Botswana

bHarvard School of Public Health, Department of Immunology and Infectious Diseases, Boston, Massachusetts, USA

cHarvard School of Public Health, Department of Biostatistics, Boston, Massachusetts, USA

dMinistry of Health, Gaborone, Botswana

eVanderbilt University School of Medicine, Vanderbilt Institute of Global Health (VIGH), Nashville, Tennessee, USA.

Correspondence to Richard G. Marlink, Harvard School of Public Health, 651 Huntington Avenue, 6th floor-FXB, Boston, MA 02115, USA. Tel: +1 617 432 4114; fax: +1 617 432 4545; e-mail:

Article Outline
Back to Top | Article Outline


The majority of the 3 million persons receiving combination antiretroviral therapy (cART) reside in resource-limited settings [1,2]. Large numbers of national initiatives offering public non-nucleoside reverse transcriptase inhibitor (NNRTI)-based cART have commenced in sub-Saharan Africa. Preliminary outcomes data from antiretroviral pilot studies in Côte d'Ivoire [3], Senegal [4], Uganda [5], Khayelitsha, South Africa [6] and Botswana [7], as well as preliminary data from larger public cART initiatives in Malawi [8,9], Botswana [10] and Zambia [11] have documented impressive efficacy outcomes among the vast majority of cART-treated adults.

In resource-rich settings, based on available data from numerous clinical trials [12–14] efavirenz is the NNRTI of choice, and is ‘preferred’ for first-line cART, along with the nucleoside reverse transcriptase inhibitors (NRTI) tenofovir and emtricitabine [12]. This recommendation is based on efficacy and more favourable tolerability data [12–18].

In resource-limited settings, the majority of cART-treated adults are women [6,7,10,11] and have been prescribed nevirapine-based cART regimens because of the potential teratogenic effects of efavirenz. Recent data have also shown that maternal nevirapine may be significantly compromised when administered to women who have recently received single-dose nevirapine for the prevention of mother-to-child HIV transmission purposes [19].

The 2NN trial [20], a large adult randomized trial, compared 1216 adults receiving stavudine plus lamuvidine with either nevirapine or efavirenz in North and South America, Australia, Europe, South Africa and Thailand. The trial found non-inferiority (nevirapine versus efavirenz) in their primary outcome of virological failure. Additional 2NN analyses [20], however, showed an association between nevirapine and higher rates of serious toxicity. The CPCRA 058 and INSIGHT study team [21], reporting randomized data from NNRTI-treated adults, however, did show higher rates of virological failure with and without resistance among nevirapine versus efavirenz-treated patients. In that study, NNRTI allocation was determined by study-determined randomization or by patient choice. Significant numbers (75%) of CPCRA 058/INSIGHT patients declined to participate in the study-determined randomization, and among those refusing, the majority (approximately 62%) chose efavirenz over nevirapine (approximately 38%). One recently published study among private sector-treated adults from South Africa [22] showed superiority of efavirenz over nevirapine, which was similar to reports from resource-rich settings. In that observational cohort of approximately 2800 adult patients, multivariate analysis showed that nevirapine-treated patients had a greater risk of virological failure [hazard ratio (HR) 1.52, 95% confidence interval (CI) 1.24–1.86], death (HR 2.17, 95% CI 1.31–3.60) and regimen discontinuation (HR 1.67, 95% CI 1.32–2.11) [22].

Family planning considerations in sub-Saharan Africa also strongly influence the choice of NNRTI, especially as pregnancy rates among cART-treated women are high and efavirenz is limited to women committed to using at least two reliable contraceptive methods. One Botswana study [23] documented pregnancy rates as high as 7.9 per 100 person-years of follow-up among cART-treated women.

Data from randomized clinical trials conducted in Africa to evaluate first-line NNRTI outcomes are lacking [24,25]. The Tshepo study was initiated in December 2002 and completed in December 2007 to evaluate the efficacy, tolerability, development of drug resistance and the optimal means to sustain short and long-term adherence among adults receiving various cART regimens in urban Botswana. ‘Tshepo’ is the Setswana word for ‘hope’.

Back to Top | Article Outline


Study design

The Tshepo study was an open-label, randomized, 3 × 2 × 2 factorial design study conducted at Princess Marina Hospital in Gaborone, Botswana, to evaluate the efficacy, tolerability and development of drug resistance of six different first-line cART regimens: zidovudine/lamivudine/nevirapine (arm A); zidovudine/lamivudine/efavirenz (arm B); zidovudine/didanosine/nevirapine (arm C); zidovudine/didanosine/efavirenz (arm D); stavudine/lamivudine/nevirapine (arm E), and stavudine/lamivudine/efavirenz (arm F). The study also compared two different adherence strategies: standard-of-care versus standard-of-care plus community-based supervision to determine the optimal means of promoting adherence among adults receiving first-line cART.

Participants were assigned in equal proportions (in an open-label, unblinded fashion) to one of six initial treatment arms and one of two adherence arms using permuted block randomization. Randomization was stratified by CD4 cell count (less than 200 cells/μl, 201–350 cells/μl) and by whether the participant had an adherence assistant. Half of the participants were enrolled in each CD4 cell count stratum, but there were no restrictions on whether they had an adherence assistant before study enrollment.

The primary endpoints of the study were: the development of virological failure with genotypic drug resistance and the development of treatment-related toxicity, as defined by the first incidence of a grade 3 or higher adverse event. Secondary endpoints were death for any reason and time to non-adherence, as estimated by an adherence rate of less than 90%.

Antiretroviral medication adherence was defined as being ‘excellent’ (>90%) based on a composite measure of three types of data: (i) patient 4-day and one-month recall; (ii) patient verbal reporting on timing of doses, number of tablets per dose and food requirements; and (iii) antiretroviral pill counts.

Initially, virological failure was defined as a confirmed plasma HIV-1 RNA level more than 5000 copies/ml at 16 or more weeks after cART initiation. An intensified adherence intervention (IAI) occurred during the month after this first elevated plasma HIV-1 RNA determination, which consisted of extensive clinic-based education and adherence counseling supplemented by community- or home-based directly observed therapy; during which the cART-treated adult chose a family member or close friend to witness at least one ARV medication dose per day, and record their dose supervision on a study-staff provided card. Home visits were conducted when/if needed. If a repeat plasma HIV-1-RNA level after this ‘intensified adherence intervention’ still exceeded 5000 copies/ml at the end of the month, the patient underwent a step change and was initiated on two different NRTI and a protease inhibitor in accordance with national treatment guidelines [26,27]. Effective as of 1 June 2007, the study virological failure definition was changed to any confirmed viraemia greater than the lower limit of detection, which was 400 copies/ml, in accordance with new medical literature [28–31] and national guidelines [27]. Genotypic resistance testing was performed using Roche ViroSeq version 2.0 (Roche Diagnostics Systems, Branchburg, New Jersey, USA) as per the manufacturer's instructions.

An independent eight-member data safety and monitoring board (DSMB) was established before study initiation. The DSMB met before the study opening and at least annually during the course of the study. On 6 April 2006, as part of the third interim analysis, the DSMB recommended discontinuing the two zidovudine/didanosine-containing study treatment arms as a result of inferiority in efficacy, as higher virological failure rates were found among participants receiving zidovudine/didanosine-containing cART compared with those receiving zidovudine/lamivudine and stavudine/lamivudine-containing cART regimens. Based on the DSMB recommendation, all cART-treated patients who were receiving zidovudine/didanosine were switched to zidovudine/lamivudine by 30 June 2006.

The study was approved by the institutional review boards of the Botswana Ministry of Health (Health Research Development Committee) and the Harvard School of Public Health (Human Subjects Committee) and written informed consent was obtained from all participants.

Back to Top | Article Outline
Study population

Adult (≥18 years of age), HIV-1 infected, cART-naive Botswana citizens who attended one of the five antiretroviral therapy (ART) screening clinics in Gaborone were approached for possible enrollment. All potentially eligible adults had to qualify for cART based on existing Botswana national antiretroviral treatment guidelines [26,27] of having an AIDS-defining illness or a CD4 cell count of 200 cells/μl or less or meet the study's eligibility criteria of a CD4 cell count between 201 and 350 cells/μl with a plasma HIV-1-RNA level greater than 55 000 copies/ml. Inclusion criteria were: haemoglobin value greater than 8.0 g/dl; absolute neutrophil count 1.0 × 103/μl or greater; aminotransferase levels less than five times the upper limit of normal; and for women of child-bearing potential, a willingness to maintain active contraception throughout the duration of the study and a negative urine pregnancy test within 14 days of study enrollment. Exclusion criteria were: poor Karnofsky performance score (40 or below); an AIDS-related malignancy other than mucocutaneous Kaposi's sarcoma; grade 2 or higher peripheral neuropathy; major psychiatric illness; and for women, actively breastfeeding or less than 6 months postpartum. In our study catchment area, standard-of-care for pregnant women involved zidovudine prophylaxis beginning at 34 weeks (later changed to 28 weeks) of gestation. Single-dose nevirapine for the prevention of mother-to-child transmission was available in the study catchment area, but the vast majority of randomly assigned women had not received it before study enrollment. Over the course of the study, protease inhibitor-containing regimens were available for all participants with confirmed virological failure, toxicities, or concomitant medical conditions that required the use of protease inhibitors.

Back to Top | Article Outline
Data collection and follow-up

Clinical and adherence assessments were performed monthly at the study clinic. To monitor treatment efficacy, CD4 cell counts (FACS Calibur flow cytometer; Becton Dickinson, San Jose, California, USA) and plasma HIV-1-RNA levels (Amplicor HIV-1 monitor test, version 1.5; Roche) were obtained at enrollment and then every 2 months for the duration of the study. Laboratory safety monitoring included comprehensive chemistry and full blood count specimens at study enrollment, then every month for the first 6 months of the study, every 2 months during months 6–12 of study participation and every 4 months during the remainder of participation. In addition, all patients had lipid chemistries performed at baseline and then every 6 months. Laboratory values were graded according to the 1994 Division of AIDS laboratory grading scale [32], except lipid chemistry values, which were graded using the Division of AIDS December 2004 grading scale [33]. Additional routine clinical assessment included peripheral neuropathy assessments every 2 months, lipodystrophy and performance assessments every 6 months, and annual screening for the presence of other sexually transmitted infections (hepatitis B and syphilis) and chest X-ray abnormalities. All women of reproductive potential had monthly urine pregnancy tests performed.

Comprehensive care for study participants was provided in accordance with existing national policy and was free of charge [26,27]. Opportunistic infections were diagnosed using available laboratory, imaging and histopathological services as well as specialist consultation. Prophylaxis for opportunistic infections included 6 months of isoniazid preventive therapy if it was determined that the participant was without clinically active tuberculosis disease and one oral double-strength cotrimoxasole tablet three times per week (or once a day) for the prevention of Pneumocystis jiroveci pneumonia when CD4 cell counts were less than 200 cells/μl.

A ‘Dear Healthcare Professional’ letter was issued by Boehringer–Ingelheim Pharmaceuticals, Inc on 5 February 2004, detailing new data pertaining to the risk of hepatotoxicity among adults initiating nevirapine-based cART [34]. This letter was adapted into a ‘Dear Participant’ letter and was disseminated to all enrolled study participants in April 2004.

Back to Top | Article Outline
Statistical considerations

To determine the sample size, a calculation was done for each of the primary objectives. Based on data from the DMP-006, DMP-043, Atlantic and COMBINE studies, we assumed that more than 50% of study participants would maintain HIV-1 plasma RNA levels of less than 400 copies/ml at one year. We also assumed a loss-to-follow-up rate of 10% over 3 years. With 600 evaluable subjects, if 50% of participants had not reached the primary endpoint by year 3 in the inferior level of two groups, we have 80% power to detect a treatment difference if the true percentage who have not failed in the superior level of the factor is 63.9% or greater; this is equivalent to a hazard ratio of 1.55 of the inferior to the superior level of the factor. With 600 evaluable subjects, if 60% (40%) of participants had not failed with resistance by year 3 in the inferior group, we had 80% power to detect a treatment difference if the true percentage who have not failed with resistance in the superior level is 73.4% (53.9%); this is equivalent to a hazard ratio of 1.65 (1.48). To ensure that there would be at least 600 evaluable participants at the end of the study, we enrolled 650 participants, allowing for the possibility of a small amount of loss to follow-up.

Primary analyses of efficacy endpoints were performed on an ‘intent-to-treat’ basis. Primary analyses of toxicity endpoints were performed on an ‘as-treated’ basis. Time-to-event methods (Kaplan–Meier survival curves including Kaplan–Meier estimates with 95% CI at one, 2 and 3 years and Cox proportional hazards models) were used to compare study participants receiving nevirapine-containing versus efavirenz-containing cART with respect to event rates for virological failure, death and toxicity. Comparisons for continuous outcomes were performed using repeated-measures analysis of variance. All statistical analyses were conducted using SAS statistical software.

Back to Top | Article Outline


Study recruitment

Between December 2002 and December 2004, 2188 patients were screened for possible enrollment at the adult Infectious Disease Care Clinic of Princess Marina Hospital and five designated local Gaborone City Council CD4+ screening clinics. Study eligibility visits and consent procedures were initiated in 898 patients. A total of 248 patients were ineligible for the following reasons: CD4 cell count between 201 and 350 cells/μl but plasma HIV-1-RNA level less than 55 000 copies/ ml (109); CD4 cell count greater than 350 cells/μl (35); active medical conditions (65) including neutropenia (19) and anaemia (18), active tuberculosis infection (nine) not on appropriate therapy and not deemed medically stable; other health-related conditions such as grade 2 or greater peripheral neuropathy, elevated liver enzymes and active/recent pregnancy (19). Thirty-six patients declined study participation and three were lost to follow-up during the screening process. A total of 650 patients were enrolled in the study.

Back to Top | Article Outline
Baseline characteristics

Overall, 650 adults were enrolled, 451 (69.4%) of whom were women. The median age was 33.3 years [interquartile range (IQR) 28.9–38.7]. Forty-three per cent had advanced World Health Organization clinical disease (stages 3 or 4) at the time of enrollment. A total of 330 (50.9%) patients were enrolled in the lower CD4 stratum, with a median CD4 cell count of 137 cells/μl, and 320 (49.1%) patients were enrolled in the upper CD4 cell count stratum (CD4 cell count between 201 and 350 cells/μl and plasma HIV-1-RNA level >55 000 copies/ml) with a median CD4 cell count of 252 cells/μl (Table 1). Baseline characteristics of patients in the nevirapine versus efavirenz arms were evenly balanced at entry, with 325 patients randomly assigned to each NNRTI arm, and within these 108 or 109 were randomly assigned to each dual-NRTI arm. A total of 325 participants was randomly assigned to the intensified adherence (community-based supervision) arm.

Back to Top | Article Outline

Study follow-up was approximately 1960 person-years, with a median follow-up time of 156 weeks (IQR 155–156). Ninety-eight per cent of all scheduled follow-up visits were attended. During the study, 54 (8.3%) of the 650 enrolled patients were lost to follow-up with regard to primary endpoint information. Twenty-six (48%) of the 54 had moved out of the study catchment area, nine (16.7%) declined further participation, and for 19 (35.2%) no further information was available despite repeated attempts by the study team to contact them. The sociodemographic and clinical characteristics of participants who were lost to follow-up did not differ from those who completed the trial.

Back to Top | Article Outline
Combination antiretroviral therapy outcomes

Analyses presented below focus on the NNRTI comparison between efavirenz and nevirapine. In all cases, the interaction terms for NNRTI × NRTI and NNRTI × adherence stratum did not approach statistical significance (all P values >0.10).

Back to Top | Article Outline
Virological failure/development of genotypic resistance

The difference by assigned NNRTI in time to the primary outcome, virological failure with resistance, was not statistically significant, log-rank P = 0.14, nevirapine versus efavirenz risk ratio (RR) 1.54 (95% CI 0.86–2.70). Rates of virological failure with resistance for patients assigned to nevirapine were 4.2% (95% CI 2.5–7.1%), 7.9% (95% CI 5.3–11.5%) and 9.6% (95% CI 6.8–13.5%) at one, 2 and 3 years, respectively, and for patients assigned to efavirenz were 0.6% (95% CI 0.1–2.6%), 4.0% (95% CI 2.3–7.0%) and 6.6% (95% CI 4.2–10.0%) at one, 2 and 3 years, respectively.

Among patients with confirmed virological failure and documented genotypic resistance mutations, the most common major NNRTI-associated mutations were as follows: K103N (34.8%), G190A (28.3%), V106 M (17.4%), Y181C (13.0%) and V108I (4.8%).

Adding death to the primary endpoint (i.e. time to virological failure with resistance or death) had no qualitative impact on the treatment comparisons. There was no difference in this endpoint for patients assigned to nevirapine compared with efavirenz; P = 0.56, or nevirapine versus efavirenz RR 1.14 (95% CI 0.74–1.75). Similarly, the comparison of time to any virological failure regardless of resistance for patients assigned to nevirapine versus efavirenz was not statistically significant: log-rank P = 0.61, RR 1.12 (95% CI 0.71–1.79).

When the time to virological failure with resistance was analysed by NNRTI assignment and sex, there was a statistical trend towards an interaction, log-rank P = 0.09. There was a trend for women receiving nevirapine-based cART to have higher virological failure rates than did women receiving efavirenz-based cART, Holm-adjusted [35] log-rank P = 0.074, nevirapine versus efavirenz RR 2.22 (95% CI 0.94–5.00). There was no difference in virologic failure rates by NNRTI assignment among men, Holm-adjusted log-rank P = 0.63; NVP vs. EFV RR 1.28 (95% CI 0.41–4.00; Fig. 1).

In a post-hoc analysis, the rate of virological failure with resistance for 152 (23.4%) patients with baseline plasma HIV-1-RNA levels greater than 500 000 copies/ml tended to be greater when compared with the 498 (76.6%) patients with baseline plasma HIV-1-RNA levels below this value: P = 0.078, RR 1.74 (95% CI 0.94–3.23; Fig. 2).

Virological suppression rates were similar among nevirapine versus efavirenz-assigned patients, Among nevirapine-assigned patients, 92.4% (95% CI 89.4–95.4%), 88.2% (95% CI 84.4–91.9%) and 90.6% (95% CI 86.9–94.2%) had undetectable plasma HIV-1-RNA levels at one, 2 and 3 years, respectively. Among efavirenz-assigned patients, 91.5% (95% CI 88.4–94.7%), 94.0% (95% CI 91.2–96.8%) and 93.6% (95% CI 90.5–96.7%) had undetectable plasma HIV-1-RNA levels at one, 2 and 3 years, respectively. The rate of early virological suppression (undetectable plasma HIV-1-RNA level by week 8) for patients assigned to nevirapine was 84.7% (95% CI 80.8–88.7%) and for patients assigned to efavirenz was 88.0% (95% CI 84.4–91.5%) and also did not differ by sex or baseline CD4 cell count stratum.

Back to Top | Article Outline
Survival/death outcomes

In total, there were 37 deaths on study. Seven of the 37 deaths (18.9%) were described as being ‘possibly related to study treatment’. Of the remaining 30 deaths, 16 (43.2%) were caused by HIV-related illnesses, 11 (29.7%) were from diseases unrelated to HIV, two (5.4%) were from accidents and one (2.7%) was a result of unknown causes. There was not a statistically significant difference in time to death between nevirapine-treated and efavirenz-treated patients, log-rank P = 0.42, nevirapine versus efavirenz RR 1.46 (95% CI 0.72–2.97). The 3-year survival rates for nevirapine versus efavirenz were 94.7% (95% CI 91.5–96.4%) and 93.1% (95% CI 89.7–95.5%), respectively.

Back to Top | Article Outline
Immunological recovery

Median annual CD4 cell increases from baseline were similar among efavirenz-treated and nevirapine-treated adults at one, 2 and 3 years (P = 0.56). Among nevirapine-assigned patients, median CD4 cell gains from baseline were 144 (IQR 75–228), 210 (IQR 115–331) and 259 (IQR 145–387) at one, 2 and 3 years, respectively. Among efavirenz-assigned patients, median CD4 cell gains from baseline were 135 (IQR 65–223), 225 (IQR 133–332) and 257 (IQR 149–388) at one, 2 and 3 years, respectively. There was a sex difference in immunological outcomes over time, with women experiencing greater CD4 cell count increases than men (P = 0.0002). Among women, median CD4 cell gains from baseline were 140 (IQR 78–236), 235 (IQR 134–352) and 274 (IQR 162–416) at one, 2 and 3 years, respectively. Among men, median CD4 cell gains from baseline were 132 (IQR 59–194), 205 (IQR 114–279), and 213 (IQR 120–342) at one, 2 and 3 years, respectively.

Back to Top | Article Outline

A total of 139 patients had 176 treatment-modifying toxicities, 90 (27.7%) nevirapine versus 49 (15.1%) efavirenz while on their initially assigned NNRTI. Nevirapine-treated patients had a shorter time to first treatment-modifying toxicity than efavirenz patients (log-rank P = 0.0002), RR 1.85 (95% CI 1.20–2.86; Fig. 3). Table 2 shows the number of patients with toxicities, by assigned NNRTI. Efavirenz-treated patients did have significantly higher rates of central nervous system (i.e. neuropsychiatric) symptoms when compared with nevirapine-treated adults, which is consistent with existing data among HIV-1 infected, subtype B, cART-treated adults. Rates of lactic acidosis were slightly higher among efavirenz-treated versus nevirapine-treated adults; additional analyses are ongoing to elucidate these findings further. The vast majority of grades 3 or 4 nevirapine-related cutaneous reactions (19 of 21, 90.5%) occurred within the first 3 months after cART initiation, with the majority occurring within the first month (18 of 19, 94.7%).

Additional subset analyses revealed no significant differences in the rate of serious hepatotoxic (grades 3 or 4) events by NNRTI assignment among women initiating nevirapine-based cART with baseline CD4 cell counts of 250 cells/μl (n = 45) or greater, 2.51 per 100 person-years compared with those initiating at baseline CD4 cell counts of less than 250 cells/μl (n = 185), 1.65 per 100 person-years (P = NS). All 45 of these women initiating nevirapine-based cART did so before the issuance of the Boehringer–Ingelheim ‘Dear Participant’ letter in February 2004.

Back to Top | Article Outline


Our study compared the effectiveness of nevirapine-based versus efavirenz-based cART among a large group of adults in Botswana. Similar to the 2NN findings [20], the Tshepo study participants receiving nevirapine-based cART had non-inferior immunological and virological outcomes when compared with those receiving efavirenz-based cART. Results from the 2NN study evaluating comparable numbers of NNRTI-treated patients did not show inferiority of nevirapine compared with efavirenz, but patients in that study had significantly higher overall virological failure rates (i.e. in the 37–44% range) compared with Tshepo study-treated patients. When analysed separately, the 2NN team [20] did find that nevirapine-treated patients from South Africa had higher virological failure rates (50.0%) when compared with efavirenz-treated patients (38.3%), with lower overall study completion by NNRTI assignment as well (48.4% versus 36.2%, respectively). The study inclusion/exclusion criteria were similar between both studies, but 2NN presented 48-week data, compared with longer-term 3-year outcomes in Tshepo. In addition, 2NN reported that regional failure rates were approximately five-fold higher than the rates reported in Tshepo.

The reasons for these higher failure rates in 2NN are most likely multifactorial and may be related to significant single-dose nevirapine exposure among female patients that compromised efficacy, lower visit intensity, definition of virological failure (i.e. lower limit of detection, greater than 50 copies/ml), and regional/site differences in the management of virological failure patients. In addition, 2NN was a multisite trial compared with Tshepo, which was conducted at only one site. In Tshepo enrolled patients had to reside and initially be committed to remain to reside within 20 km of the study clinic for all 3 years of the study. 2NN did not appear to have a similar requirement, which may have contributed to their higher virological failure rates.

Unlike 2NN, Tshepo results showed a statistical trend in virological failure with resistance rates by sex and NNRTI together, with women receiving nevirapine-based cART having higher rates of failure than those who received efavirenz-based cART. This sex-by-treatment interaction was only marginally significant (Holm-adjusted P = 0.074). To investigate the sensitivity of these results to the change in primary endpoint definition (effective 1 June 2007; 7 months before study completion), we performed a separate analysis including as virological failures only those patients who met the failure definition using our initial/old definition, namely having a confirmed plasma HIV-1-RNA level greater than 5000 copies/ml. In this analysis, the sex-by-treatment interaction was no longer even marginally significant. There were six patients who met the new definition, by having a confirmed plasma HIV-1-RNA level greater than 400 copies/ml, four nevirapine treated and two efavirenz treated. Only two of these patients, both efavirenz treated, met our old virological failure definition (>5000 copies/ml), whereas the remaining four nevirapine-treated patients did not.

Reasons for the statistical trend towards sex differences in the Tshepo study may also be related to NNRTI tolerability, as higher proportions of women experienced moderate/severe nevirapine-associated toxicity. This toxicity could have negatively influenced antiretroviral medication adherence rates. The genotypic resistance patterns among patients failing NNRTI-based cART were similar to published literature from resource-rich settings [36,37]. These findings show a trend towards higher virological failure rates among women receiving nevirapine-based treatment. The findings must be balanced, however, with the potential risk of efavirenz-related teratogenicity, especially in the light of the high pregnancy rates that are being reported among cART-treated women in the region [23].

Approximately 13% of deaths on study were deemed ‘possibly related to study medication’, and of these, lactic acidosis was the major cause. All three women who died as a result of severe lactic acidosis were overweight (body mass index >25) [38] and received efavirenz. Additional gene association studies and the contribution of oxidant stress as it relates to adipogenesis are ongoing in order to characterize these potentially ‘at-risk’ individuals better.

There were also significant tolerability differences. Nevirapine-treated adults had higher rates of treatment-modifying toxicity compared with efavirenz-treated adults. The most common nevirapine-associated treatment-modifying toxicities were cutaneous hypersensitivity reactions and hepatotoxicity, with rates of each being higher than expected when compared with cART-treated adults in western Europe and the United States. Additional studies are planned looking more in depth at the risk factors associated with the development of hepatotoxicity.

This current study has certain limitations. The rates of virological failure were most likely influenced by certain key factors: namely, the inferiority of zidovudine/didanosine, as identified by the DSMB, and our change in the virological failure definition after the majority of patients had reached greater than two-thirds of their total study follow-up. In addition, our study was under-powered to detect significant differences as our original power calculations were based on anticipated virological failure rates of approximately 50% (based on available published literature from resource-rich settings), and our actual event rates were lower than predicted. The effects of zidovudine/didanosine should have been equally distributed between the NNRTI arms in our randomized design.

Back to Top | Article Outline


Tshepo-treated patients had impressive immunological and virological outcomes, and no significant differences were observed by randomized NNRTI. Nevirapine-treated women, however, had a marginally statistically significant trend towards higher virological failure rates with resistance when compared with efavirenz-treated women. There were no differences among men. There were also significant tolerability differences, with nevirapine-treated adults having higher treatment-modifying toxicity rates when compared with those receiving efavirenz-based cART. Nevirapine-based cART can continue to be offered to women in the region as long as routine safety monitoring chemistries are done, and ideally periodic plasma HIV-1-RNA levels can be performed. Efavirenz-treated women have a trend towards more favourable virological outcomes, but this must be balanced with the potential risk of efavirenz-related teratogenicity, especially in the light of the high pregnancy rates being reported among cART-treated women in the region.

Back to Top | Article Outline


The authors would like to acknowledge formally the Botswana Ministry of Health, the Princess Marina Hospital administration, outpatient adult Infectious Disease Care Clinic and inpatient medical ward teams, the entire Adult Antiretroviral Treatment and Drug Resistance (Tshepo) study team and their funder, the Bristol-Myers Squibb foundation for support of this research initiative. The authors also want to acknowledge and thank all adult study participants. Finally, they would like to thank Erika Färdig and Meredith Feir (Administration, Harvard School of Public Health, Boston, MA, USA) for assistance with this manuscript.

Sponsorship: The project described was supported by the following research grants from the National Institute of Allergy and Infectious Diseases, K23AI073141 (Principal Investigator: C.W.W.) grant evaluating the ‘Risk Factors for the Development of Lactic Acidosis and Pancreatitis Among HAART-Treated Adults in Botswana’ and P30AI060354 (Principal Investigator: C.W.W.), Harvard Center for AIDS Research (CFAR) grant evaluating the ‘Risk factors for the development of nevirapine-associated toxicity in Southern Africa’. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

Conflicts of interest: None.

Back to Top | Article Outline


1. World Health Organization. Priority interventions: HIV/AIDS prevention, treatment and care in the health sector, September 2008. Geneva: World Health Organization; 2008. ISBN 978 92 4 159696 1.
2. Pan American Health Organization. Guidelines for the implementation of reliable and efficient diagnostic HIV testing, region of the Americas. 2008. Available at: Accessed: 7 November 2009.
3. Djomand G, Roels T, Ellerbrock T, Hanson D, Diomande F, Monga B, et al. Virologic and immunologic outcomes and programmatic challenges of an antiretroviral treatment pilot project in Abidjan, Cote d'Ivoire. AIDS 2003; 17(Suppl. 3):S5–S15.
4. Laurent C, Diakhaté N, Gueye NF, Touré MA, Sow PS, Faye MA, et al. The Senegalese government's highly active antiretroviral therapy initiative: an 18-month follow-up study. AIDS 2002; 16:1363–1370.
5. Weidle PJ, Malamba S, Mwebaze R, Sozi C, Rukundo G, Downing R, et al. Assessment of a pilot antiretroviral drug therapy programme in Uganda: patients' response, survival, and drug resistance. Lancet 2002; 360:34–40.
6. Coetzee D, Hildebrand K, Boulle A, Maartens G, Louis F, Labatala V, et al. Outcomes after two years of providing antiretroviral treatment in Khayelitsha, South Africa. AIDS 2004; 18:887–895.
7. Wester CW, Kim S, Bussmann H, Avalos A, Ndwapi N, Peter TF, et al. Initial response to highly active antiretroviral therapy in HIV-1C-infected adults in a public sector treatment program in Botswana. J Acquir Immune Defic Syndr 2005; 40:336–343.
8. Ferradini L, Jeannin A, Pinoges L, Izopet J, Odhiambo D, Mankhambo L, et al. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Lancet 2006; 367:1335–1342.
9. Harries AD, Gomani P, Teck R, de Teck OA, Bakali E, Zachariah R, et al. Monitoring the response to antiretroviral therapy in resource-poor settings: the Malawi model. Trans R Soc Trop Med Hyg 2004; 98:695–701.
10. Bussmann H, Wester CW, Thomas A, Novitsky V, Okezie R, Muzenda T, et al. Five-year outcomes of initial patients treated in Botswana's National Antiretroviral Treatment Program. AIDS 2008; 22:1–9.
11. Stringer JS, Zulu I, Levy J, Stringer EM, Mwango A, Chi BH, et al. Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes. JAMA 2006; 296:782–793.
12. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. 3 November 2008; 1–139. Available at: Accessed: 7 November 2009. pp. 26–29.
13. Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003; 349:2293–2303.
14. Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, Stanford J, et al. Efavirenz plus zidovudine and lamuvidine, efavirenz plus indinavir, and indinavir plus zidovudine and lamuvidine in the treatment of HIV-1 infection in adults. N Engl J Med 1999; 341:1865–1873.
15. O'Brien ME, Clark RA, Besch CL, Myers L, Kissinger P. Patterns and correlates of discontinuation of the initial HAART regimen in an urban outpatient cohort. J Acquir Immune Defic Syndr 2003; 34:407–414.
16. Keiser O, Fellay J, Opravil M, Hirsch HH, Hirschel B, Bernasconi E, et al. Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification. Antiviral Ther 2007; 12:1157–1164.
17. Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr 2004; 35:538–539.
18. Dieterich DT, Robinson PA, Love J, Stern JO. Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. Clin Infect Dis 2004; 38(Suppl. 2):S80–S89.
19. Lockman S, Shapiro RL, Smeaton LM, Wester C, Thior I, Stevens L, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med 2007; 356:135–147.
20. van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363:1253–1263.
21. van den Berg-Wolf M, Hullsiek KH, Peng G, Kozal MJ, Novak RM, Chen L, et al. Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1 infected persons. HIV Clin Trials 2008; 9:324–336.
22. Nachega JB, Hislop M, Dowdy DW, Gallant JE, Chaisson RE, Regensberg L, Maartens G. Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS 2008; 22:2117–2125.
23. Bussmann H, Wester CW, Wester CN, Lekoko B, Okezie O, Thomas AM, et al. Pregnancy rates and birth outcomes among women on efavirenz-containing HAART in Botswana. J Acquir Immune Defic Syndr 2007; 45:269–273.
24. Hogg R, May M, Philips AN, Costagliola D, Sterne JAC, Sabin CA, et al. ART-CC Analysis and Writing Committee members. Rates of disease progression according to initial highly active antiretroviral therapy regimen: a collaborative analysis of 12 prospective cohort studies. J Infect Dis 2006; 194:612–622.
25. Hughes MD. Initial treatment of HIV infection: randomized trials with clinical end points are still needed. J Infect Dis 2006; 194:542–544.
26. Ministry of Health, Botswana. Guidelines on antiretroviral treatment, 2002 version. Gaborone, Botswana: Ministry of Health; 2002.
27. Ministry of Health, Botswana. Guidelines on antiretroviral treatment, 2005 version. Gaborone, Botswana: Ministry of Health; 2005.
28. Weverling GJ, Lange JM, Jurriaans S, Prins JM, Lukashov VV, Notermans DW, et al. Alternative multidrug regimen provides improved suppression of HIV-1 replication over triple therapy. AIDS 1998; 12:F117–F122.
29. Polis MA, Sidorov IA, Yoder C, Jankelevich S, Metcalf J, Mueller BU, et al. Correlation between reduction in plasma HIV-1 RNA concentration 1 week after start of antiretroviral treatment and longer-term efficacy. Lancet 2001; 358:1760–1765.
30. Ghani AC, Ferguson NM, Fraser C, Donnelly CA, Danner S, Reiss P, et al. Viral replication under combination antiretroviral therapy: a comparison of four different regimens. J Acquir Immune Defic Syndr 2002; 30:167–176.
31. Maggiolo F, Migliorino M, Pirali A, Pravettoni G, Caprioli S, Suter F. Duration of viral suppression in patients on stable therapy for HIV-1 infection is predicted by plasma HIV RNA level after 1 month of treatment. J Acquir Immune Defic Syndr 2000; 25:36–43.
32. Division of AIDS, NIAID. Division of AIDS table for grading severity of adult adverse experiences. Rockville, MD: National Institute of Allergy and Infectious Diseases; 1994.
33. Division of AIDS, NIAID. Division of AIDS table for grading severity of adult adverse experiences. Rockville, MD: National Institute of Allergy and Infectious Diseases; 2004.
34. Boehringer Ingelheim Pharmaceuticals, Inc. “Important and urgent advance information”. Dear Doctor/Dear Pharmacist letter; entitled “Re: Identification of patients at particular risk of serious hepatic and cutaneous reactions associated with Viramune (nevirapine) 200 mg tablets and 50 mg/5 ml oral suspension.” dated 11 May 2004; and signed by Mark Hopley, MD, Medical Director.
35. Holm S. A simple sequentially rejective multiple test procedure. Scand J Statistics 1979; 6:65–70.
36. Rhee S-Y, Gonzales MJ, Kantor R, Betts BJ, Ravela J, Shafer RW. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucl Acids Res 2003; 31:298–303.
37. Shafer RW. Rationale and uses of a public HIV drug-resistance database. J Infect Dis 2006; 194(Suppl. 1):S51–S58.
38. Wester CW, Okezie OA, Thomas AM, Bussmann H, Moyo S, Muzenda T, et al. Higher than expected rates of lactic acidosis among highly active antiretroviral therapy-treated women in Botswana: preliminary results from a large randomized clinical trial. J Acquir Immune Defic Syndr 2007; 46:318–322.

HAART; HIV/AIDS; nevirapine versus efavirenz; non-nucleoside reverse transcriptase inhibitors; randomized clinical trial; sub-Saharan Africa

© 2010 Lippincott Williams & Wilkins, Inc.