Bussmann, Hermann MD, MPH*†; Wester, C William MD*†¶; Thomas, Ann PhD, SM§; Novitsky, Vladimir PhD*†; Okezie, Reginald MD*; Muzenda, Tanaka MD*; Gaolathe, Tendani MD*‡; Ndwapi, Ndwapi MD*‡; Mawoko, Norah Pharm D*; Widenfelt, Erik BSc*; Moyo, Sikhulile MSc, MPH*; Musonda, Rosemary PhD*†; Mine, Madisa PhD‡; Makhema, Joseph MBChB*†; Moffat, Howard MD, FRCP*†; Essex, Max DVM, PhD*†; DeGruttola, Victor DSc§; Marlink, Richard G MD*†
In recent years, combination antiretroviral therapy (cART) has been introduced on a large scale throughout sub-Saharan Africa. Initial reports from antiretroviral (ARV) pilot studies in Côte d'Ivoire,1 Senegal,2 Uganda,3 Khayelitsha, South Africa,4 and Botswana5 and preliminary data from larger public cART initiatives in Malawi6,7 and Zambia8 have been very encouraging and reported impressive clinical, immunologic, and virologic responses among the vast majority of cART-treated individuals. These African cART outcomes have surpassed previous expectations and offer hope for the vast numbers of people in dire need of ARV treatment.9-12
These published outcomes also raise numerous issues that need to be addressed to further improve ARV treatment protocols. Important considerations include the selection of optimal regimens, especially with regard to tolerability and efficacy; the determination of the optimal time for cART initiation; the optimal means to promote and sustain ARV medication adherence; and the issue of drug resistance among persons infected with non-B subtypes.13-15 Data from randomized clinical trials conducted in Africa to evaluate these critical questions are very much needed.16-18
The “Tshepo” Study was begun in December 2002 in urban Botswana to compare 6 different cART regimens with regard to their efficacy and tolerability and to describe the development and overall kinetics of drug resistance. The study was also designed to identify the optimal means of promoting adherence by evaluating an intensified adherence strategy [community-based directly observed therapy (Com-DOT)] versus the standard of care (SOC). We herein report outcomes among adults randomized to zidovudine (ZDV)/didanosine (ddI)-based cART versus ZDV/lamivudine (3TC)- (given as Lamzid) or stavudine (d4T)/3TC-based cART after the discontinuation of the ZDV/ddI-containing study treatment arms due to documented inferiority in efficacy as part of the study's third interim Data Safety Monitoring Board (DSMB) review. The word Tshepo means “hope” in Setswana.
The Tshepo Study is an open-label, randomized, 3 × 2 × 2 factorial design study conducted at Princess Marina Hospital (PMH) in Gaborone, Botswana. This study was designed to address many important questions by evaluating the efficacy, tolerability, and the development of drug resistance of 6 different first-line cART regimens. The evaluated regimens were as follows: ZDV/3TC/nevirapine (NVP) (arm A), ZDV/3TC/efavirenz (EFV) (arm B), ZDV/ddI/NVP (arm C), ZDV/ddI/EFV (arm D), d4T/3TC/NVP (arm E), and d4T/3TC/EFV (arm F). The study also compared 2 different adherence strategies SOC versus SOC plus a community-based supervision (Com-DOT) to determine the better method for promoting adherence among treatment-naive adults initiating cART.
The primary end points of the study were as follows: (1) the development of virologic failure with significant drug resistance and (2) the development of treatment-related toxicity, as defined by first incidence of a grade 3 or higher adverse event. Secondary end points were the time to occurrence of AIDS-defining events and/or death for any reason.
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.
Adult (18 years and older), HIV-infected, cART-naive Botswana citizens who attended 1 of the 5 ARV treatment-screening clinics in Gaborone were approached for possible enrollment. All potentially eligible adults had to qualify for cART, based on existing Botswana National ARV Treatment guidelines19 of having an AIDS-defining illness and/or CD4+ T-cell count of equal or less than 200 cells per cubic millimeter or meet this study's upper CD4 stratum eligibility criteria, which was a CD4+ T-cell count between 201 and 350 cells per cubic millimeter with plasma HIV-1 RNA level greater than 55,000 copies per milliliter. Potentially eligible adults also had to reside within the study catchment area for the duration of the study. Other inclusion criteria were as follows: hemoglobin value greater than 8.0 g/dL; absolute neutrophil count greater than or equal to 1.0 × 103/mm3; aminotransferase levels less than 5 times the upper limit of normal; serum alkaline phosphatase level less than 3 times the upper limits 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 as follows: a poor Karnofsky performance score (40 or below); an AIDS-related malignancy other than mucocutaneous Kaposi sarcoma; a grade 2 or higher peripheral neuropathy; a major psychiatric illness; and for women, actively breast-feeding and/or less than 6 months postpartum.
Additional treatment steps, defined as protease inhibitor (PI)-containing regimens, were available for all participants with confirmed virologic failure, toxicities, or concomitant medical conditions that required the use of PIs.
Data Collection and Follow-Up
Clinical and adherence assessments were done monthly at the study clinic. To monitor treatment efficacy, CD4+ T-cell counts (FACSCalibur flow cytometer; Becton Dickinson, San Jose, CA) and plasma HIV-1 RNA levels (Amplicor HIV-1 Monitor Test, version 1.5; Roche Diagnostics Systems, Branchburg, NJ) were obtained at enrollment and then every 2 months for the duration of the study. Laboratory safety monitoring included comprehensive chemistry and complete blood count (hematology) specimens at study enrollment, then every month for the first 6 months of the study, every 2 months during the months 6-12 of study participation, and every 4 months during the remainder of participation, for safety monitoring purposes. In addition, all patients had lipid chemistries (total, low-density lipoprotein, and high-density lipoprotein cholesterol; glucose; and serum triglycerides) performed at the time of study initiation and then every 6 months for the duration of the study. Laboratory values were graded according to the 1994 Division of AIDS (DAIDS) laboratory grading scale, except lipid chemistry values that were graded using the DAIDS December 2004 grading scale. 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), proteinuria/glycosuria, and chest x-ray abnormalities. Patients also received an ophthalmologic evaluation at baseline, which was repeated at least every 2 years on study. All female patients had baseline Papanicolaou smears performed, which were repeated at least annually or more frequently as clinically indicated. Colposcopic examinations were performed when clinically indicated. 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 free of charge.20,21 Opportunistic infections (OIs) were diagnosed using available laboratory, imaging, and histopathologic services and specialist consultation. Pulmonary tuberculosis (TB) and extrapulmonary TB were diagnosed using acid-fast bacilli staining, cerebrospinal fluid microscopy, and radiographic imaging (chest radiography, computed tomography scanning, and ultrasound). Pneumocystis jiroveci (formerly carinii) pneumonia was diagnosed using clinical expertise and radiographic imaging (chest radiography). Cryptococcal meningitis was ascertained by india ink staining of the cerebrospinal fluid. Cytomegalovirus retinitis was diagnosed by fundoscopic examinations, which were performed by specially trained ophthalmologists. Malignancies (invasive cervical carcinoma, Kaposi sarcoma, and non-Hodgkin lymphoma) were diagnosed by histology and expert pathologist and/or oncologist review. Clinical expertise alone was used to diagnose Candida esophagitis and herpes zoster. Prophylaxis for OIs included 6 months of isoniazid plus pyridoxine (vitamin B6) preventative therapy if determined that participant was without clinically active TB disease and 1 oral double-strength cotrimoxasole tablet 3 times per week (or once daily) for the prevention of P. jiroveci pneumonia if the CD4+ T-cell count was less than 200 cells per cubic millimeter.
ARV medication adherence was defined as being “excellent” (greater than 90%) based on a composite adherence measure that included the following: (1) patient 4 day recall, (2) patient 1 month recall, (3) patient ARV self-demonstration (including verbal reporting on timing of doses, number of tablets per dose, and food requirements), and (4) ARV pill counts.
Initially, virologic failure was defined as a confirmed plasma HIV-1 RNA level of greater than 5000 copies per milliliter at 16 or more weeks after cART initiation. If the repeat plasma HIV-1 RNA level after an intensified adherence intervention still exceeded 5000 copies per milliliter, the patient underwent a step change and was initiated on 2 different nucleoside reverse transcriptase inhibitors (NRTIs) and a PI in accordance with the 2002 and 2005 Botswana National ARV Treatment guidelines.19,21 Effective April 1, 2006, the study virologic failure definition was changed to any confirmed viremia (greater than the lower limit of detection, which is 400 copies/mL) in accordance with new literature22-24 and existing national guidelines.21 All participants with confirmed virologic failure underwent an intensified adherence intervention, which included an initial adherence assessment and adherence education, followed by a 2- to 4-week period of Com-DOT. A repeat viral load measurement was done at the end of the intervention. Genotypic resistance testing was done using Roche ViroSeq v 2.0, an integrated system for sequence-based analysis of drug resistance mutations in HIV-1, as per the manufacturer's instructions. In cases of first-line cART regimen virologic failures, the study physician was blinded to genotypic resistance results.
On April 6, 2006, as part of the third interim analysis, our independent DSMB recommended discontinuing the ZDV/ddI-containing study treatment arms due to inferiority in efficacy, specifically higher virologic failure rates among cohort-treated participants receiving ZDV/ddI-containing cART compared with those receiving ZDV/3TC- and d4T/3TC-containing cART regimens. The Board recommended that all cART-treated patients who were receiving the dual-NRTI combination of ZDV/ddI be switched to ZDV/3TC.
All primary analyses and the majority of secondary analyses were performed on an “intent-to-treat” basis. Kaplan-Meier (K-M) survival curves including 95% confidence intervals (CIs) at 1 and 2 years and Cox proportional hazards models were used to compare study participants receiving ZDV/ddI-containing cART with patients who received cART regimens that did not contain ZDV/ddI, with respect to event rates for virologic failure, death, toxicities, OIs, and nonadherence. For our analyses, observations were censored on April 1, 2006, or when the participant died or was lost to follow-up, if before that date. All statistical analyses were conducted using SAS software.
Between December 2002 and 2004, 2188 patients were screened for possible study enrollment at the adult Infectious Disease Care Clinic (IDCC) of PMH and 4 designated local Gaborone City Council “CD4+-screening” clinics. In total, 650 adults were eligible, consented, and enrolled in the study. Figure 1 summarizes the main reasons for nonenrollment into the study. In short, 823 patients were referred to the Botswana National ARV Program at the adjacent adult PMH-IDCC for continued longitudinal care due to our study team reaching its daily limit in total number of enrolled patients. Five hundred sixty-nine patients were not eligible according to the study protocol. Of these 569 patients, 210 had a Karnofsky score equal to or below 40 and 62 patients were deemed ineligible based on the presence of the following active medical conditions and/or laboratory abnormalities, namely, neutropenia (19), anemia (18), active TB infection not yet on appropriate therapy (9), and other health-related conditions (16) such as grade 2 or greater peripheral neuropathy or elevated liver enzymes. An additional 109 patients were not eligible due to virologic criteria, namely, having a CD4+ count between 201 and 350 cells per cubic millimeter but having a plasma viral load below 55,000 copies per milliliter as our viral load cutoff was based on existing World Health Organization (WHO) and Department of Health and Human Services guidelines at the time the study was designed. One hundred seven patients had CD4+ count of greater than 350 cells per cubic millimeter (35) or were not antiretroviral therapy (ART) naive (72). Thirty-nine patients declined study participation (36) or were lost to follow-up (3) during the screening process.
Of the 650 enrolled adults, 451 were females (69.4%). Forty-three percent had advanced WHO clinical disease (stage 3 or stage 4). Table 1 summarizes the key baseline characteristics.
Baseline characteristics of patients in the ZDV/ddI arms versus the other 4 arms (d4T/3TC and ZDV/3TC containing) were evenly balanced at entry. Three hundred twenty-five participants were randomized to the intensified adherence (Com-DOT) arm. Three hundred thirty patients (50.9%) were enrolled in the lower CD4+ T-cell count stratum with a median CD4+ T-cell count of 137 cells per cubic millimeter. Three hundred twenty patients (49.1%) were enrolled in the upper CD4+ T-cell count stratum (CD4+ T-cell count value between 201 and 350 cells per cubic millimeter and plasma HIV-1 RNA above 55,000 copies/mL) with a median CD4+ T-cell count of 252 cells per cubic millimeter.
The amount of study follow-up was 1308 person-years, with a median follow-up time of 104 weeks [interquartile ratio (IQR) 78-136]. Ninety-eight percent of all scheduled follow-up visits were attended. As of April 1, 2006, 4 years and 3 months into the study, 31 of the 650 enrolled patients were lost to follow-up with regard to primary end point information. Of the 31 patients, 18 (58%) had moved out of the study catchment area; 6 (19%) declined further participation; and for 7 (23%), no further information was available despite repeated attempts by the study team to contact them. The overall loss to follow-up rates were 2.4% (CI: 1.4% to 3.9%) and 4.1% (CI: 2.6% to 5.2%) at 1 and 2 years, respectively. The sociodemographic and clinical characteristics of participants who were lost to follow-up did not differ from those participants who completed the trial.
Highly Active Antiretroviral Therapy Outcomes
The median increase in CD4+ T-cell count was 137 cells per cubic millimeter at 1 year (IQR 74-223) and 199 cells per cubic millimeter at 2 years (IQR 112-322). There was a significant difference by treatment arms with a median CD4+ T-cell gain from baseline in the ZDV/ddI arm of 106 (IQR 34-176) cells per cubic millimeter and in the non-ZDV/ddI arm of 156 (IQR 94-242) cells per cubic millimeter at 1 year and 163 (IQR 70-250) cells per cubic millimeter at 2 years, (P = 0.0001). CD4+ T-cell count increases were significantly higher in women (P = 0.0094). No significant difference was found in relation to anemia (baseline hemoglobin), body mass index, or age greater than 40 years. Concordant virologic and immunologic responses were found in 75%, 76%, and 81% of participants at 6, 12, and 24 months, respectively. At 12 and 24 months, significantly more patients in the ZDV/ddI group showed discordant responses. Additional analyses are planned to look more in depth at potential reasons for a small subset of patients who have discordant immunologic and virologic responses.
Figure 2 shows the proportion of all study participants who had undetectable plasma HIV-1 RNA levels at weeks 8, 24, 48, 72, and 96, stratified by whether they were receiving ZDV/ddI-containing cART or non-ZDV/ddI-containing (ZDV/3TC or d4T/3TC based) cART. Three hundred sixty-one of study participants (56%) had undetectable (<400 copies/mL) plasma HIV-1 RNA levels at 4 weeks after cART initiation. Of those whose HIV-1 RNA suppressed to undetectable levels at 8 weeks after cART initiation, 70.8% (64.1%-76.4%) receiving ZDV/ddI-based cART and 85.6% (81.9%-88.7%) receiving non-ZDV/ddI-based cART remained consistently suppressed at 1 year. At 2 years, the percentages remaining consistently suppressed were 57.6% (50.4%-64.2%) for ZDV/ddI arms and 78.5% (74.0%-82.2%) for the non-ZDV/ddI arms. Following DSMB recommendations, the ZDV/ddI-containing cART arms were discontinued (after the cutoff date for this analysis); and all patients substituted 3TC for ddI due to inferiority in primary end point, namely, virologic failure.
As of April 1, 2006, 55 study participants (8.5%) had developed virologic failure, as defined by the study protocol of whom 52 cases were successfully genotyped. In 2 cases, no genotyping data were available due to a missed confirmatory visit, and in 1 case, viral amplification was unsuccessful. Thirty-eight of the available 52 genotypes (70%) were found to have virologic failure with primary genotypic resistance mutations. Figure 3 is a K-M plot of time to first virologic failure with resistance. Rates of virologic failure with resistance were significantly higher in the ZDV/ddI-containing treatment arms when compared with the non-ZDV/ddI-containing treatment arms (P value < 0.0001). At 1 year, 5.3% (3.0%-9.4%) of patients receiving ZDV/ddI-containing cART had virologic failure with resistance compared with 1.0% (0.1%-1.7%) of those receiving non-ZDV/ddI-containing cART. At 2 years, 13.5% (9.2%-19.4%) of those receiving ZDV/ddI-containing cART and 3.2% (1.8%-5.8%) of patients receiving non-ZDV/ddI-containing cART had virologic failure with resistance.
Of 38 cases of virologic failure with resistance mutations, 25 cases occurred in NVP-containing regimens versus 13 cases of EFV-containing regimens. NRTI mutations were present in 27 cases. Of note, a unique pattern of thymidine analogue mutations (TAM) mutations, namely, the 67N 70R 215Y pathway was found in patients failing ZDV/ddI-containing first-line cART at the time of virologic failure. Among all patients failing ZDV/ddI-containing cART, the 2 most common resistance genotypes were the 67N 70R 215Y genotype, present in 7 of 19 cases (37%), and a single T215Y mutation, present in 5 of 19 of cases (26%). No 210W or 219Q genotypes were present among analyzed failures. With the exception of 3 virologic failure cases, namely, 1 patient having the 67N 70R 215Y genotype and 2 cases having an isolated M41L mutation, all other failing patients having primary NRTI mutations also had concomitant primary nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations.
As of April 2006, 43 patients had been changed from first-line study treatment to PI-based cART. Reasons for the change to second- or third-line PI-based cART included the following: virologic failure (63%), pregnancy protection (23%), and severe ARV-related toxicity (14%), the majority of which were due to moderate-severe symptomatic hyperlactatemia or lactic acidosis syndrome.25
The mean body weight increase after 2 years of cART was 6.2 kg for patients with pre-existing wasting syndrome and 3.0 kg for patients without existing HIV-associated wasting syndrome at the time of study enrollment.
As of April 1, 2006, 32 enrolled study participants (5%) had died. Eight of these 32 deaths (25%) occurred within the first 3 months after cART initiation. Among theses 8 cases, 4 were due to advanced AIDS, 2 were non-AIDS related, and 2 were possibly related to ARV treatment. Overall, of the 32 deaths, 7 (23%) were deemed “possibly related to ARV treatment,” with 4 related to lactic acidosis/pancreatitis, 2 related to traditional medication use/abuse with possible underlying pancreatitis, and 1 from NVP-associated fulminant hepatic failure potentially exacerbated by isoniazid that the patient was taking for TB prophylaxis. Twelve of the 32 deaths (37.5%) were due to an OI.
The K-M 1- and 2-year survival estimates were 96.6% (CI: 94.8% to 97.7%) and 95.4% (CI: 93.5% to 96.8%), respectively, for the entire cohort. There were no statistically significant differences across the 2 pooled treatment groups, ZDV/ddI treated versus non-ZDV/ddI treated (P = 0.93). In univariate analysis, death was significantly related to anemia (baseline hemoglobin value <10.0 g/dL), poor performance status (Karnofsky score less than 90), and HIV-associated wasting syndrome (body mass index <18.5 kg/m2).
Safety and Tolerability
Overall, 208 clinically relevant grades 3 and 4 serious adverse events occurred in 99 patients, excluding laboratory events that did not change clinical management such as amylase, gamma glutaryl transaminase, and alkaline phosphatase elevations. These serious adverse events were distributed equally among the pooled treatment groups (ZDV/ddI treated versus ZDV/3TC and d4T/3TC treated, log-rank P = 0.2575). At 1 and 2 years, 11.3% (9.1%-14.0%) and 14.5% (11.9%-17.5%) of patients had had a grade 3 or grade 4 serious adverse event, respectively.
Thirty-one patients (14.8%) in the ZDV/ddI group and 89 patients (19.8%) in the non-ZDV/ddI group had 140 treatment-modifying toxicities (log-rank P = 0.0647), with lipodystrophy (50), neutropenia (23), anemia (22), and cutaneous hypersensitivity reactions (16) being the most common (Table 2). At 1 year, 8.9% (5.8%-13.6%) of patients receiving ZDV/ddI-containing cART had a treatment-modifying toxicity compared with 12.2% (9.5%-15.7%) of those who received non-ZDV/ddI-containing cART. At 2 years, 12.6% (8.8%-18.0%) of patients who received ZDV/ddI-containing cART and 16.7% (13.8%-20.7%) of those receiving non-ZDV/ddI-containing cART had a treatment-modifying toxicity.
One hundred six incident OIs were diagnosed in 93 study participants. The most common OIs included (1) varicella zoster virus infection (shingles) (40 patients), (2) pulmonary TB (36 patients), and (3) extrapulmonary TB (13 patients, 11 with miliary/disseminated TB and 2 with TB meningitis) (Table 3). At 1 year, 12.8% (9.0%-18.1%) of patients receiving ZDV/ddI-containing cART had had an OI compared with 7.5% (5.4%-10.5%) of patients who received non-ZDV/ddI-containing cART. At 2 years, 16.6% (12.0%-22.2%) of patients receiving ZDV/ddI-containing cART and 11.9% (9.1%-15.6%) of patients who received non-ZDV/ddI-containing cART had had an OI. The log-rank test by treatment group was statistically significant (P = 0.042), with ZDV/ddI-treated patients having a shorter time to first OI compared with non-ZDV/ddI-treated patients.
Medication adherence was reported to be excellent (ie, greater than 90% at all measured time points, as per monthly clinic adherence assessments) in 89.8% of study participants after 1 year of follow-up and 81.2% after 2 years of study follow-up. There was a statistically significant difference by dual-NRTI combination, with ZDV/ddI-treated patients having a shorter time to first report of nonadherence when compared with those receiving ZDV/3TC- and d4T/3TC-based cART regimens (P = 0.03), and anecdotally, study participants frequently expressed difficulties in following the specific food-related instructions when taking the non-enteric-coated ddI. Pooled treatment group analysis also showed statistically significant differences in adherence by sex, with males having a shorter time to nonadherence (P = 0.006).
We report herein our 2-year findings among adult patients enrolled in Botswana's ongoing Tshepo Study, one of the first large-scale, randomized, clinical trials focusing on cART outcomes to be conducted in sub-Saharan Africa. Our interim study results, backed by an impressive retention rate of study participants during the 2 years of follow-up, demonstrate an overall excellent immunologic and virologic response to NRTI/NNRTI regimens among HIV-1C-infected adults. The low virologic failure rate with resistance mutations, 1.0% at year 1 and 3.2% at year 2, in the 4 non-ZDV/ddI-containing arms is superior to results obtained from cART-treated cohorts in industrialized countries.26
Our data clearly demonstrate the inferiority of the dual-NRTI combination of ZDV/ddI compared with the dual-NRTI combinations of ZDV/3TC and d4T/3TC, when given together with either NVP or EFV in HIV-1C-infected adults. These findings prompted the closure of the ZDV/ddI-containing treatment arms as recommended by our DSMB. Interestingly, a novel reverse transcriptase 67N 70R 215Y genotype was the predominant TAM pathway among HIV-1C-infected individuals treated with ZDV/ddI as part of their first-line regimen. This mixture of TAM-1 (41L/210W/215Y) and TAM-2 (67N/70R/215F/219Q) pathways might represent an HIV-1 subtype C-specific resistance pathway to first-line ZDV/ddI-containing regimens.27
Although recommended as an alternative first-line regimen by WHO guidelines at the time our randomized trial began, information on the efficacy of the dual-NRTI combination of ZDV/ddI in NNRTI-containing cART regimens has been scarce.28-32 Our findings of a novel TAM resistance pathway selected by HIV-1C in the presence of ZDV/ddI make a compelling case against the use of this dual-NRTI combination for first-line cART in the developing world and support the most recent WHO33 and international guidelines,34 which now recommend that lamuvidine (3TC) (or emtricitabine [FTC]) be given with either tenofovir (TDF) or zidovudine (ZDV) for first-line cART with NVP or EFV.
ARV treatment programs are rapidly scaling up in resource-limited settings in sub-Saharan Africa. Most programs have chosen either Triommune (d4T/3TC/NVP)-based or Combivir/Lamzid (ZDV/3TC)-based cART as the first-line regimen.35,36 ddI still plays an important role for second-line cART regimens,37 especially where newer NRTIs (abacavir) and nucleotide reverse transcriptase inhibitors (tenofovir) are not uniformly available, largely due to high cost. Additional studies are needed to characterize the activity of ZDV/ddI-based cART regimens given with a PI as the second-line regimen in settings where d4T and 3TC combinations are used as the NRTI backbones in first-line regimens.38
The 1- (96.6%) and 2-year (95.4%) survival outcomes among cART-treated adults in this large cohort are impressive when compared with data from other cohorts in resource-limited settings.39 Our study did not include patients who were severely ill at baseline, which may have certainly influenced our overall favorable clinical outcomes (ie, low mortality rates), but as a team, we did make every effort to include ill patients as evidenced by the numbers with advanced immunosuppression, advanced WHO clinical stage (3 and/or 4), and high plasma HIV-1 RNA levels at baseline. Nearly a quarter of all deaths were deemed “possibly related to study treatment” with the majority of ARV-related deaths related to severe mitochondrial toxicities, especially lactic acidosis and/or pancreatitis, emphasizing the importance of replacing d4T with a safer alternative. Cohort data are still needed to characterize long-term cART outcomes in the region especially as comorbid medical illness, and particularly, cardiovascular causes of death comprise an increasing percentage of deaths, especially among predominantly NNRTI non-PI-treated adults.
The sustainability of ART programs largely depends on the tolerability of ARV medication. Although a number of studies in Africa have reported toxicity outcomes and regimen switch rates, these studies used different regimens, observation times, and severity grading systems. A comprehensive analysis of toxicities related to the individual ARV drugs used in this study is currently being performed. The interim 2-year outcome data of this controlled clinical trial show that all 6 first-line cART regimens are well tolerated. The overall rate of treatment-modifying toxicity was low when compared with results from observational studies followed in the region.40-43 This may, in part, reflect the fact that many Tshepo Study participants initiated cART at higher baseline CD4+ T-cell counts than in other cohorts. ddI-related toxicities such as pancreatitis, peripheral neuropathy, and diarrhea were rarely a reason for treatment modification in the ZDV/ddI-containing treatment arm. Importantly, the occurrence of lipodystrophy and lactic acidosis was disproportionately more frequent among patients in the pooled d4T-containing treatment arms. This finding is consistent with the result of other studies that have shown higher rates of mitochondrial toxicity among d4T-treated patients.41,44
Incident OI rates are important markers for understanding the clinical course of treated HIV disease and for the development of treatment guidelines and planning of health services. Unfortunately, these conditions have often not been reported in a standardized fashion. Limited diagnostic facilities, high TB rates, and difficulties defining immune reconstitution inflammatory syndrome make the task more difficult for African settings.4,5,40 Patients on ZDV/ddI-containing cART experienced significantly higher OI rates in the first 2 years of ARV treatment as compared with those on non-ZDV/ddI regimens. This finding is most probably a consequence of the higher virologic failure rate and the poorer immunologic recovery among patients in the ZDV/ddI arm of the study.
Of note, 7 of our intensively monitored participants developed cancer-related diagnoses. As cART-treated adults survive longer in the region, improved diagnostic capacity at the referral hospital level and education and training to enable health care providers to more efficiently diagnose and manage these potentially life-threatening conditions will be important regional needs over the next 5-10 years.
We also report excellent 1-year adherence rates, which support rates reported by other ART programs in Africa.8,11,45-47 However, the decline in medication adherence in the second year, especially among male participants, is a concern. As the long-term sustainability of cART programs in Africa largely depends upon sustained cART adherence rates, it is of paramount importance for health care personnel to provide ongoing ARV adherence support. This support must be continually adapted to meet patients' needs, while at the same time addressing the needs of those most at risk for poor adherence, with particular attention paid to men and patients with ongoing psychosocial, financial, or physical needs.
In summary, interim results from the Tshepo Study show the importance and feasibility of conducting large clinical research initiatives in resource-limited settings. Our preliminary findings document remarkable immunologic and virologic responses to first-line PI-sparing cART regimens and excellent cohort retention rates. These outcomes surpass many reported in western Europe and the United States. Continued long-term cohort follow-up is needed as are new randomized clinical trials designed to address important regional considerations such as optimal first-line cART regimens, the optimal timing of cART initiation, and the kinetics and development of drug resistance, which seems to differ from what has been reported among HIV-1 subtype B-infected cART-treated individuals.
We would like to formally acknowledge the Botswana Ministry of Health and the Princess Marina Hospital administration and staff, especially the outpatient adult IDCC and inpatient Medical Ward teams. We would like to thank our sponsor, the Bristol-Myers Squibb Foundation, Secure the Future, for their multifaceted support of this research initiative. We also very much thank all study participants. Lastly, we would like to acknowledge and personally thank Erika Färdig (Administration, Harvard School of Public Health, Boston, MA) for her administrative oversight, review of this article, and overall technical assistance and expertise.
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