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1.  Assessing the effect of HAART on change in quality of life among HIV-infected women 
Background
The impact of highly active antiretroviral therapy (HAART) on health-related quality of life (QOL) of HIV-1 infected individuals in large prospective cohorts has not been well studied.
Objective
To assess the effect of HAART on QOL by comparing HIV-infected women using HAART with HIV-infected women remaining HAART naïve in the Women's Interagency HIV Study (WIHS), a multicenter prospective cohort study begun in 1994 in the US.
Methods
A 1:1 matching with equivalent (≤ 0.1%) propensity scores for predicting HAART initiation was implemented and 458 pairs were obtained. HAART effects were assessed using pattern mixture models. The changes of nine QOL domain scores and one summary score derived from a shortened version of the MOS-HIV from initial values were used as study outcomes.
Results
The background covariates of the treatment groups were well-balanced after propensity score matching. The 916 matched subjects had a mean age of 38.5 years and 42% had a history of AIDS diagnosis. The participants contributed a total of 4,292 person visits with a median follow-up time of 4 years. In the bivariate analyses with only HAART use and time as covariates, HAART was associated with short-term improvements of 4 QOL domains: role functioning, social functioning, pain and perceived health index. After adjusting for demographic, socioeconomic, biological and clinical variables, HAART had small but significant short-term improvements on changes in summary QOL (mean change: 3.25; P = 0.02), role functioning (6.99; P < 0.01), social functioning (5.74; P < 0.01), cognitive functioning (3.59; P = 0.03), pain (6.73; P < 0.01), health perception (3.67; P = 0.03) and perceived health index (4.87; P < 0.01). These QOL scores typically remained stable or declined over additional follow-up and there was no indication that HAART modified these trends.
Conclusion
Our study demonstrated significant short-term HAART effects on most QOL domains, but additional use of HAART did not modify long-term trends. These changes could be attributed to the direct effect of HAART and indirect HAART effect mediated through clinical changes.
doi:10.1186/1742-6405-3-6
PMCID: PMC1459186  PMID: 16549012
2.  Early severe morbidity and resource utilization in South African adults on antiretroviral therapy 
Background
High rates of mortality and morbidity have been described in sub-Saharan African patients within the first few months of starting highly active antiretroviral therapy (HAART). There is limited data on the causes of early morbidity on HAART and the associated resource utilization.
Methods
A cross-sectional study was conducted of medical admissions at a secondary-level hospital in Cape Town, South Africa. Patients on HAART were identified from a register and HIV-infected patients not on HAART were matched by gender, month of admission, and age group to correspond with the first admission of each case. Primary reasons for admission were determined by chart review. Direct health care costs were determined from the provider's perspective.
Results
There were 53 in the HAART group with 70 admissions and 53 in the no-HAART group with 60 admissions. The median duration of HAART was 1 month (interquartile range 1-3 months). Median baseline CD4 count in the HAART group was 57 × 106 cells/L (IQR 15-115). The primary reasons for admission in the HAART group were more likely to be due to adverse drug reactions and less likely to be due to AIDS events than the no-HAART group (34% versus 7%; p < 0.001 and 39% versus 63%; p = 0.005 respectively). Immune reconstitution inflammatory syndrome was the primary reason for admission in 10% of the HAART group. Lengths of hospital stay per admission and inpatient survival were not significantly different between the two groups. Five of the 15 deaths in the HAART group were due to IRIS or adverse drug reactions. Median costs per admission of diagnostic and therapeutic services (laboratory investigations, radiology, intravenous fluids and blood, and non-ART medications) were higher in the HAART group compared with the no-HAART group (US$190 versus US$111; p = 0.001), but the more expensive non-curative costs (overhead, capital, and clinical staff) were not significantly different (US$1199 versus US$1128; p = 0.525).
Conclusions
Causes of early morbidity are different and more complex in HIV-infected patients on HAART. This results in greater resource utilization of diagnostic and therapeutic services.
doi:10.1186/1471-2334-9-205
PMCID: PMC2803481  PMID: 20003472
3.  Public-Health and Individual Approaches to Antiretroviral Therapy: Township South Africa and Switzerland Compared 
PLoS Medicine  2008;5(7):e148.
Background
The provision of highly active antiretroviral therapy (HAART) in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. We compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting HAART in South Africa and Switzerland.
Methods and Findings
We analysed data from the Swiss HIV Cohort Study and two HAART programmes in townships of Cape Town, South Africa. We included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded intravenous drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4+ T cell counts were 80 cells/μl in South Africa and 204 cells/μl in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%–97%) in South Africa and 96% (94%–97%) in Switzerland, and 26% (22%–29%) and 27% (24%–31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of HAART: adjusted hazard ratios were 5.90 (95% CI 1.81–19.2) during months 1–3 and 1.77 (0.90–3.50) during months 4–24.
Conclusions
Compared to the highly individualised approach in Switzerland, programmatic HAART in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to HAART and improve the prognosis of patients who start HAART with advanced disease.
Comparing HIV treatment in Switzerland, where drug selection is individualized, and South Africa, where a programmatic approach is used, Matthias Egger and colleagues find similar virologic outcomes over two years.
Editors' Summary
Background.
Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since the first reported case in 1981, and more than 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected people died within 10 years of becoming infected. Then, in 1996, highly active antiretroviral therapy (HAART)—a combination of several antiretroviral drugs—was developed. Now, in resource-rich countries, clinicians provide individually tailored care for HIV-infected people by prescribing combinations of antiretroviral drugs chosen from more than 20 approved medicines. The approach to treatment of HIV in developed countries typically also includes frequent monitoring of the amount of virus in patients' blood (viral load), viral resistance testing (to see whether any viruses are resistant to specific antiretroviral drugs), and regular CD4 cell counts (an indication of immune-system health). Since the implementation of these interventions, the health and life expectancy of people with HIV has improved dramatically in these countries.
Why Was This Study Done?
The history of HIV care in resource-poor countries has been very different. Initially, these countries could not afford to provide HAART for their populations. In 2003, however, governments, international agencies, and funding bodies began to implement plans to increase HAART coverage in developing countries. By December 2006, more than a quarter of the HIV-infected people in low- and middle-income countries who urgently needed treatment were receiving HAART. However, instead of individualized treatment, HAART programs in developing countries follow a public-health approach developed by the World Health Organization. That is, drug regimens, clinical decision-making, and clinical and laboratory monitoring are all standardized. This public-health approach takes into account the realities of under-resourced health systems, but is it as effective as the individualized approach? The researchers addressed this question by comparing virologic responses (the effect of treatment on the viral load), changes to first-line (initial) therapy, and deaths in patients receiving HAART in South Africa (public-health approach) and in Switzerland (individualized approach).
What Did the Researchers Do and Find?
The researchers analyzed data collected since 2001 from more than 2,000 patients enrolled in HAART programs in two townships (Gugulethu and Khayelitsha) in Cape Town, South Africa, and from more than 1,000 patients enrolled in the Swiss HIV Cohort Study, a nationwide study of HIV-infected people. The patients in South Africa, who had a lower starting CD4 cell count and were more likely to have advanced AIDS than the patients in Switzerland, started their treatment for HIV infection with one of four first-line therapies, and about a quarter changed to a second-line therapy during the study. By contrast, 36 first-line regimens were used in Switzerland and half the patients changed to a different regimen. Despite these differences, the viral load was greatly reduced within a year in virtually all the patients and viral rebound (an increased viral load after a low measurement) developed within 2 years in a quarter of the patients in both countries. However, more patients died in South Africa than in Switzerland, particularly during the first 3 months of therapy.
What Do These Findings Mean?
These findings suggest that the public-health approach to HAART practiced in South Africa is as effective in terms of virologic outcomes as the individualized approach practiced in Switzerland. This is reassuring because it suggests that “antiretroviral anarchy” (the unregulated use of antiretroviral drugs, interruptions in drug supplies, and the lack of treatment monitoring), which is likely to lead to the emergence of viral resistance, is not happening in South Africa as some experts feared it might. Thus, these findings support the continued rollout of the public-health approach to HAART in resource-poor countries. Conversely, they also suggest that a more standardized approach to HAART could be taken in Switzerland (and in other industrialized countries) without compromising its effectiveness. Finally, the higher mortality in South Africa than in Switzerland, which partly reflects the many patients in South Africa in desperate need of HAART and their more advanced disease at the start of therapy, suggests that HIV-infected patients in South Africa and in other resource-limited countries would benefit from earlier initiation of therapy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050148.
The World Health Organization provides information about universal access to HIV treatment (in several languages) and on its recommendations for a public-health approach to antiretroviral therapy for HIV infection
More details on the Swiss HIV Cohort Study and on the studies in Gugulethu and Khayelitsha are available
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including detailed information about antiretroviral therapy and links to treatment guidelines for various countries
Information is available from Avert, an international AIDS charity, on HIV and AIDS around the world and on providing AIDS drug treatment for millions
doi:10.1371/journal.pmed.0050148
PMCID: PMC2443185  PMID: 18613745
4.  Highly active antiretroviral treatment and health related quality of life in South African adults with human immunodeficiency virus infection: A cross-sectional analytical study 
BMC Public Health  2007;7:244.
Background
Health Related Quality of Life (HRQoL) is an important outcome in times of Highly Active Antiretroviral Treatment (HAART). We compared the HRQoL of HIV positive patients receiving HAART with those awaiting treatment in public sector facilities in the Free State province in South Africa.
Methods
A stratified random sample of 371 patients receiving or awaiting HAART were interviewed and the EuroQol-profile, EuroQol-index and Visual Analogue Scale (VAS) were compared. Independent associations between these outcomes and HAART, socio-demographic, clinical and health service variables were estimated using linear and ordinal logistic regression, adjusted for intra-clinic clustering of outcomes.
Results
Patients receiving HAART reported better HRQoL for 3 of the 5 EuroQol-dimensions, for the VAS score and for the EuroQol index in bivariable analysis. They had a higher mean EuroQol index (0.11 difference, 95% confidence interval [CI] 0.04; 0.23), and were more likely to have a higher index (odds ratio 1.9, 95% CI 1.1; 1.3), compared to those awaiting HAART, in multivariate analysis. Higher mean VAS scores were reported for patients who were receiving HAART (6.5 difference, 95% CI 1.3; 11.7), were employed (9.1, 95% CI 4.3; 13.7) or were female (4.7, 95% CI 0.79; 8.5).
Conclusion
HAART was associated with improved HRQoL in patients enrolled in a public sector treatment program in South Africa. Our finding that the EuroQol instrument was sensitive to HAART supports its use in future evaluation of HIV/AIDS care in South Africa. Longitudinal studies are needed to evaluate changes in individuals' HRQoL.
doi:10.1186/1471-2458-7-244
PMCID: PMC2194770  PMID: 17854510
5.  Cost-Effectiveness of Highly Active Antiretroviral Therapy in South Africa 
PLoS Medicine  2005;3(1):e4.
Background
Little information exists on the impact of highly active antiretroviral therapy (HAART) on health-care provision in South Africa despite increasing scale-up of access to HAART and gradual reduction in HAART prices.
Methods and Findings
Use and cost of services for 265 HIV-infected adults without AIDS (World Health Organization [WHO] stage 1, 2, or 3) and 27 with AIDS (WHO stage 4) receiving HAART between 1995 and 2000 in Cape Town were compared with HIV-infected controls matched for baseline WHO stage, CD4 count, age, and socioeconomic status, who did not receive antiretroviral therapy (ART; No-ART group). Costs of service provision (January 2004 prices, US$1 = 7.6 Rand) included local unit costs, and two scenarios for HAART prices for WHO recommended first-line regimens: scenario 1 used current South African public-sector ART drug prices of $730 per patient-year (PPY), whereas scenario 2 was based on the anticipated public-sector price for locally manufactured drug of $181 PPY. All analyses are presented in terms of patients without AIDS and patients with AIDS.
For patients without AIDS, the mean number of inpatient days PPY was 1.08 (95% confidence interval [CI]: 0.97–1.19) for the HAART group versus 3.73 (95% CI: 3.55–3.97) for the No-ART group, and 8.71 (95% CI: 8.40–9.03) versus 4.35 (95% CI: 4.12–5.61), respectively, for mean number of outpatient visits PPY. Average service provision PPY was $950 for the No-ART group versus $1,342 and $793 PPY for the HAART group for scenario 1 and 2, respectively, whereas the incremental cost per life-year gained (LYG) was $1,622 for scenario 1 and $675 for scenario 2. For patients with AIDS, mean inpatients days PPY was 2.04 (95% CI: 1.63–2.52) for the HAART versus 15.36 (95% CI: 13.97–16.85) for the No-ART group. Mean outpatient visits PPY was 7.62 (95% CI: 6.81–8.49) compared with 6.60 (95% CI: 5.69–7.62) respectively. Average service provision PPY was $3,520 for the No-ART group versus $1,513 and $964 for the HAART group for scenario 1 and 2, respectively, whereas the incremental cost per LYG was cost saving for both scenarios. In a sensitivity analysis based on the lower (25%) and upper (75%) interquartile range survival percentiles, the incremental cost per LYG ranged from $1,557 to $1,772 for the group without AIDS and from cost saving to $111 for patients with AIDS.
Conclusion
HAART is a cost-effective intervention in South Africa, and cost saving when HAART prices are further reduced. Our estimates, however, were based on direct costs, and as such the actual cost saving might have been underestimated if indirect costs were also included.
Healthcare costs for HIV-infected South African adults on HAART compared with costs for HIV-infected controls not on HAART. Authors conclude HAART is cost effective.
doi:10.1371/journal.pmed.0030004
PMCID: PMC1298940  PMID: 16318413
6.  Influenza-Related Mortality Among Adults Aged 25–54 Years With AIDS in South Africa and the United States of America 
In the absence of highly active therapy antiretroviral (HAART), adults with AIDS experience substantially elevated influenza-associated mortality in South Africa and the United States. This elevated mortality risk declined with widespread HAART introduction in the United States but did not disappear entirely. These data support increased access to HAART and influenza vaccination for human immunodeficiency virus–infected adults globally.
Background. Data are limited on human immunodeficiency virus (HIV)–associated influenza burden in sub-Saharan Africa and the impact of highly active antiretroviral therapy (HAART). We compared influenza-related mortality in adults with AIDS in South Africa and the United States in the pre-HAART era and evaluated mortality trends after HAART introduction in the United States.
Methods. Monthly all-cause and pneumonia and influenza (P&I) mortality rates were compiled for adults with AIDS aged 25–54 years in South Africa (1998–2005) and the United States (pre-HAART era, 1987–1994; HAART era, 1997–2005). We estimated influenza-related deaths as excess mortality above a model baseline during influenza epidemic periods. Influenza-related mortality rates in adults with AIDS were compared with rates for age peers in the general population and adults ≥65 years old.
Results. In the United States before HAART, influenza-related mortality rates in adults with AIDS were 150 (95% confidence interval [CI], 49–460) and 208 (95% CI, 74–583) times greater than in the general population for all-cause and P&I deaths, respectively, and 2.5 (95% CI, 0.9–7.2) and 4.1 (95% CI, 1.4–13) times higher than in elderly adults. After HAART introduction , influenza-related mortality in adults with AIDS dropped 3–6-fold but remained elevated compared with the general population (all-cause relative risk [RR], 44 [95% CI, 16–121]); P&I RR, 73 [95% CI, 47–113]). Influenza-related mortality in South African adults with AIDS in recent years was similar to that in the United States in the pre-HAART era.
Conclusions. Adults with AIDS experience substantially elevated influenza-associated mortality, which declines with widespread HAART introduction but does not disappear. These data support increased access to HAART and influenza vaccination for HIV-infected adults.
doi:10.1093/cid/cis549
PMCID: PMC3657519  PMID: 22715173
7.  Antiretroviral treatment and quality of life in Africans living with HIV: 12-month follow-up in Burkina Faso 
Introduction
The scale-up of highly active antiretroviral therapy (HAART) has led to a significant improvement in survival of the HIV-positive patient but its effects on health-related quality of life (HRQOL) are less known and context-dependent. Our aim was to assess the temporal changes and factors associated with HRQOL among HIV-positive adults initiating HAART in Burkina Faso.
Methods
HIV-positive people initiating HAART were prospectively included and followed over a one-year period in three HIV clinics of Ouagadougou. HRQOL was assessed at baseline and at each follow-up visit using physical (PHS) and mental (MHS) summary scores derived from the Medical Outcome Study 36-Item short-form health survey (MOS SF-36) questionnaire. Toxicity related to HAART modification and self-reported symptoms were recorded during follow-up visits. Determinants associated with baseline and changes in both scores over a one-year period were assessed using a mixed linear model.
Results
A total of 344 patients were included. Their median age at baseline was 37 years [interquartile range (IQR) 30–44] and their median CD4 count was 181 cells/mm3 (IQR 97–269). The mean [standard deviation (SD)] PHS score increased from 45.4 (11.1) at baseline to 60.0 (3.1) at 12 months (p<10−4) and the mean (SD) MHS score from 42.2 (8.7) to 43.9 (3.4) (p<10−2). After one year of treatment, patients that experienced on average two symptoms during follow-up presented with significantly lower PHS (63.9) and MHS (43.8) scores compared to patients that presented no symptoms with PHS and MHS of 68.2 (p<10−4) and 45.3 (p<10−3), respectively.
Discussion
The use of HAART was associated with a significant increase in both physical and mental aspects of the HRQOL over a 12-month period in this urban African population. Perceived symptoms experienced during follow-up visits were associated with a significant impairment in HRQOL. The appropriate and timely management of reported symptoms during the follow-up of HAART-treated patients is a key component to restore HRQOL.
doi:10.7448/IAS.16.1.18867
PMCID: PMC3871830  PMID: 24369739
quality of life; HIV/AIDS; antiretroviral treatment; Burkina Faso; sub-Saharan Africa
8.  Pregnancy and Virologic Response to Antiretroviral Therapy in South Africa 
PLoS ONE  2011;6(8):e22778.
Background
Although women of reproductive age are the largest group of HIV-infected individuals in sub-Saharan Africa, little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in that setting. We examined the effect of incident pregnancy after HAART initiation on virologic response to HAART.
Methods and Findings
We evaluated a prospective clinical cohort of adult women who initiated HAART in Johannesburg, South Africa between 1 April 2004 and 30 September 2009, and followed up until an event, death, transfer, drop-out, or administrative end of follow-up on 31 March 2010. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study; final sample size for analysis was 5,494 women. Main exposure was incident pregnancy, experienced by 541 women; main outcome was virologic failure, defined as a failure to suppress virus to ≤400 copies/ml by six months or virologic rebound >400 copies/ml thereafter. We calculated adjusted hazard ratios using marginal structural Cox proportional hazards models and weighted lifetable analysis to calculate adjusted five-year risk differences. The weighted hazard ratio for the effect of pregnancy on time to virologic failure was 1.34 (95% confidence limit [CL] 1.02, 1.78). Sensitivity analyses generally confirmed these main results.
Conclusions
Incident pregnancy after HAART initiation was associated with modest increases in both relative and absolute risks of virologic failure, although uncontrolled confounding cannot be ruled out. Nonetheless, these results reinforce that family planning is an essential part of care for HIV-positive women in sub-Saharan Africa. More work is needed to confirm these findings and to explore specific etiologic pathways by which such effects may operate.
doi:10.1371/journal.pone.0022778
PMCID: PMC3149058  PMID: 21829650
9.  Treatment strategies for Kaposi sarcoma in Sub-Saharan Africa: Challenges and Opportunities 
Current opinion in oncology  2011;23(5):463-468.
Purpose of review
The purpose of this review is to summarize recent published literature on treatment of AIDS-associated Kaposi sarcoma (KS), the most common HIV-associated malignancy and a leading cancer diagnosis in sub-Saharan Africa (SSA), and to highlight the challenges faced in treating KS in this resource-limited environment.
Recent findings
There are few prospective clinical trials for KS treatment in SSA, along with a relatively poor cancer treatment infrastructure, leading to late diagnosis and poor access to therapy. The only prospectively-randomized trial of chemotherapy compared antiretroviral therapy (HAART) alone to HAART with combination chemotherapy with doxorubicin, bleomycin and vincristine (ABV), and documented a significantly higher rate of tumor regression for the combination along with improvement in quality of life and no adverse effects on HIV control. Other studies suggest that gemcitabine may be an active second-line chemotherapeutic agent after failure of HAART and ABV and suggest that AIDS-associated KS in children may respond well to HAART with chemotherapy. There are also (primarily retrospective) data suggesting a beneficial effect of HAART on KS, but some evidence for KS as a manifestation of immune reconstitution inflammatory syndrome.
Summary
Opportunities and need exist for prospective research to establish evidence-based guidelines for the most effective treatments for KS in SSA.
doi:10.1097/CCO.0b013e328349428d
PMCID: PMC3465839  PMID: 21681092
Kaposi sarcoma; chemotherapy; sub-Saharan Africa; AIDS-associated cancer; HIV/AIDS
10.  The Impact of Revised PMTCT Guidelines: A View From a Public Sector ARV Clinic in Cape Town, South Africa 
Background:
In April 2010, revised Prevention of Mother-to-Child Transmission guidelines were implemented in South Africa, advising fast-tracked lifelong highly active antiretroviral therapy (HAART) initiation at a higher CD4 count (≤350 cells per microliter). This study describes the impact of these changes on the management of pregnant women who initiated HAART at Tygerberg Hospital, Cape Town.
Methods:
We conducted a retrospective review of all women who initiated HAART in pregnancy at the Tygerberg Hospital between January 2008 and December 2010. Year cohorts were compared.
Results:
Two hundred and fifty HIV-infected women were included in the study and stratified by HAART initiation year: 2008:N = 82, 2009:N = 71, 2010:N = 97. There were no differences between the groups in age or parity. Median booking CD4 count was 155 cells per microliter [interquartile range (IQR) 107–187], 157 cells per microliter (IQR 104–206) and 208 cells per microliter (IQR 138–270), respectively (P < 0.001). Median gestation at HAART initiation was 31 weeks (IQR 27–35), 30 weeks (IQR 26–34), and 25 weeks (IQR 21–31; P < 0.001). HIV transmission rates were 3/65 (4.6%), 4/57 (7.0%), and 0/90 (0.0%; P = 0.021). Women <8 weeks on HAART before delivery were more likely to transmit than women ≥8 weeks [odds ratio 9.69; 95% confidence interval 1.66 to 56.58; P = 0.017]. Ninety-four (37.6%) women were lost to follow-up, 18.4% within 28 days of delivery.
Conclusions:
The positive impact of the new Prevention of Mother-to-Child Transmission program is evident. A longer duration of HAART before delivery was associated with less transmission. However, the lost to follow-up rates remain concerning. Further research is needed to better understand the reasons for nonadherence and mechanisms to improve support for these women.
doi:10.1097/QAI.0b013e31828bb721
PMCID: PMC3707566  PMID: 23422849
HIV; antenatal; antiretroviral therapy; mother-to-child transmission; South Africa
11.  A randomized controlled trial of HAART versus HAART and chemotherapy in therapy-naïve patients with HIV-associated Kaposi sarcoma in South Africa 
Background
The optimal approach to HIV-associated KS (HIV-KS) in sub-Saharan Africa is unknown. With large-scale rollout of highly active antiretroviral therapy (HAART) in South Africa, we hypothesized survival in HIV-KS would improve and administration of chemotherapy in addition to HAART would be feasible and improve KS-specific outcomes.
Methods
We conducted a randomized, controlled, open-label trial with intention-to-treat analysis. Treatment-naïve patients from King Edward VIII Hospital, Durban, South Africa, a public-sector tertiary referral center, with HIV-KS, but no symptomatic visceral disease or fungating lesions requiring urgent chemotherapy, were randomized to HAART alone or HAART and chemotherapy (CXT). HAART arm received stavudine, lamivudine and nevirapine (Triomune®); CXT arm received Triomune® plus bleomycin, doxorubicin, and vincristine (ABV) every 3 weeks. When ABV was not available, oral etoposide (50-100 mg days 1-21 of a 28 day cycle) was substituted. Primary outcome was overall KS response using AIDS Clinical Trial Group criteria 12 months after HAART initiation. Secondary comparisons included: time to response, progression-free survival, overall survival, adverse events, HIV control, CD4 reconstitution, adherence and quality-of-life.
Results
59 subjects were randomized to HAART, 53 to CXT. 12-month overall KS response was 39% in the HAART arm and 66% in the CXT arm (difference 27%; 95% CI 9%-43%, p=0.005). At 12 months, 77% were alive (no survival difference between arms, p=0.49), 82% had HIV viral load <50 copies/mL without difference between arms, (p=0.47); CD4 counts and QOL measures improved in all patients.
Conclusions
HAART with chemotherapy produced higher overall KS response over 12 months, while HAART alone provided similar improvement in survival and select measures of morbidity. In Africa, with high prevalence of HIV and HHV-8 and limited resources, HAART alone provides important benefit in patients with HIV-KS.
doi:10.1097/QAI.0b013e318251aedd
PMCID: PMC3360837  PMID: 22395672
Kaposi sarcoma; acquired immunodeficiency syndrome; human immunodeficiency virus; highly active antiretroviral therapy; South Africa
12.  Determinants of optimal adherence over time to antiretroviral therapy amongst HIV positive adults in South Africa: A longitudinal study 
AIDS and behavior  2011;15(7):1465-1474.
Highly active antiretroviral therapy (HAART) requires strict adherence to achieve optimal clinical and survival benefits. A study was done to explore the factors affecting HAART adherence among HIV positive adults by reviewing routinely collected patient information in the Centre for the AIDS Programme of Research in South Africa’s (CAPRISA) AIDS Treatment Programme. Records of 688 patients enrolled between 2004 and 2006 were analysed. Patients were considered adherent if they had taken at least 95% of their prescribed drugs. Generalized estimating equations were used to analyse the data. The results showed that HAART adherence increased over time, however, the rate of increase differed by some of the socio-demographic and behavioural characteristics of the patients. For instance, HAART adherence increased in both urban and rural treatment sites over time, but the rate of increase was higher in the rural site. This helped identify sub-populations, such as the urban population, that required ongoing adherence counseling.
doi:10.1007/s10461-010-9688-x
PMCID: PMC3056165  PMID: 20352319
adherence; HAART; generalized estimating equations (GEE); longitudinal study; pill count approach
13.  Incident Pregnancy and Time to Death or AIDS among HIV-Positive Women Receiving Antiretroviral Therapy 
PLoS ONE  2013;8(3):e58117.
Background
Little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in sub-Saharan Africa. We examined the effect of incident pregnancy after HAART initiation on clinical response to HAART.
Methods
We evaluated a prospective clinical cohort of adult women initiating HAART in Johannesburg, South Africa between 1 April 2004 and 31 March 2011, and followed up until an event, transfer, drop-out, or administrative end of follow-up on 30 September 2011. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study. Main exposure was having experienced pregnancy after HAART initiation; main outcome was death and (separately) death or new AIDS event. We calculated adjusted hazard ratios (HRs) and 95% confidence limits (CL) using marginal structural Cox proportional hazards models.
Results
The study included 7,534 women, and 20,813 person-years of follow-up; 918 women had at least one recognized pregnancy during follow-up. For death alone, the weighted (adjusted) HR was 0.84 (95% CL 0.44, 1.60). Sensitivity analyses confirmed main results, and results were similar for analysis of death or new AIDS event. Incident pregnancy was associated with a substantially reduced hazard of drop-out (HR = 0.62, 95% CL 0.51, 0.75).
Conclusions
Recognized incident pregnancy after HAART initiation was not associated with increases in hazard of clinical events, but was associated with a decreased hazard of drop-out. High rates of pregnancy after initiation of HAART may point to a need to better integrate family planning services into clinical care for HIV-infected women.
doi:10.1371/journal.pone.0058117
PMCID: PMC3592862  PMID: 23520489
14.  Decreased sexual risk behavior in the era of HAART among HIV-infected urban and rural South Africans attending primary care clinics 
AIDS (London, England)  2010;24(17):2687-2696.
Objective
In light of increasing access to highly active antiretroviral treatment (HAART) in sub-Saharan Africa, we conducted a longitudinal study to assess the impact of HAART on sexual risk behaviors among HIV-infected South Africans in urban and rural primary care clinics.
Design
Prospective observational cohort study.
Methods
We conducted a cohort study at rural and urban primary care HIV clinics in South Africa consisting of 1544 men and 4719 women enrolled from 2003–2010, representing 19703 clinic visits. The primary outcomes were being sexually active, unprotected sex, and >1 sex partner and were evaluated at six monthly intervals. Generalized estimated equations assessed the impact of HAART on sexual risk behaviors.
Results
Among 6263 HIV-infected men and women, over a third (37.2%) initiated HAART during study follow-up. In comparison to pre-HAART follow-up, visits while receiving HAART were associated with a decrease in those reporting being sexually active (AOR: 0.86 [95% CI: 0.78–0.95]). Unprotected sex and having >1 sex partner were reduced at visits following HAART initiation compared to pre-HAART visits (AOR: 0.40 [95% CI: 0.34–0.46] and AOR: 0.20 [95% CI: 0.14–0.29], respectively).
Conclusions
Sexual risk behavior significantly decreased following HAART initiation among HIV-infected South African men and women in primary care programs. The further expansion of antiretroviral treatment programs could enhance HIV prevention efforts in Africa.
doi:10.1097/QAD.0b013e32833e78d4
PMCID: PMC3130627  PMID: 20808202
South Africa; HAART; antiretroviral therapy; sexual behavior; HIV transmission; AIDS; HIV
15.  Human Immunodeficiency Virus Infection and Hodgkin's Lymphoma in South Africa: An Emerging Problem 
Advances in Hematology  2011;2011:578163.
Hodgkin's lymphoma (HL) occurs with increasing frequency in human-immunodeficiency-virus-(HIV-) infected individuals. The natural history and behaviour of HIV-HL is different, being more atypical and aggressive. The association between HIV and HL appears to be primarily EBV driven. HAART use does not significantly impact on the incidence of HL. Indeed, the risk of HL has increased in the post-HAART era. However, the advent of HAART has brought renewed hope, allowing standard therapeutic options to be used more optimally, with better treatment outcomes. Despite the renewed optimism, the overall survival of HIV-HL patients remains less favourable than that in HIV-seronegative patients. This is particularly true in sub-Saharan Africa, where there is a significant burden of HIV/AIDS and where more than half the patients are HAART naive at diagnosis of HL. The similarities and differences of a South African cohort of HIV-HL are presented in this paper.
doi:10.1155/2011/578163
PMCID: PMC3038417  PMID: 21331149
16.  Effects of highly active antiretroviral therapy and its adherence on herpes zoster incidence: a longitudinal cohort study 
Background
Herpes zoster (HZ) is common among HIV-infected individuals, but the impacts of highly active antiretroviral therapy (HAART) and HAART adherence on HZ risk have not been well studied.
Methods
The effects of HAART and HAART adherence on HZ incidence were evaluated by comparing HIV-infected women on HAART (HAART use group) with the HIV-infected women remaining HAART naïve (HAART naïve group) in the Women’s Interagency HIV Study (WIHS). A 1:1 matching with propensity score for predicting HAART initiation was conducted to balance background covariates at index visit, including HIV disease stage. Kaplan-Meier method was used to compare the risk of HZ development between the matched pairs. Cox proportional hazard models were used to assess the effects of HAART and HAART adherence on HZ incidence.
Results
Through propensity score matching, 389 pairs of participants were identified and they contributed 3,909 person years after matching. The background covariates were similar between the matched pairs at the index visit. The participants had a mean age around 39 years old, and about 61% of them were Black and 22% were Latina. No significant difference in HZ risk was observed between the HAART use group and the HAART naïve group during the first year of follow-up in any analyses. In the univariate analysis, the HAART use group had marginally lower HZ risk (Hazard Ratio (HR): 0.72; 95% Confidence Interval (CI): 0.48-1.1) over the entire follow-up period. However, women with a HAART adherence level of ≥95% had significantly lower HZ risk (HR: 0.54; 95% CI: 0.31, 0.94) compared to the HAART naïve women. The association remained significant after adjusting for quality of life score and acyclovir use, but it attenuated and was no longer statistically significant after adjusting for an intermediate variable, either CD4+ T cell counts or HIV viral load.
Conclusions
Among adult women, we observed a significant preventive effect of long-term HAART use on HZ incidence when a HAART adherence level of ≥95% was attained, and this effect was mediated through reduction of HIV viral load and improvement of CD4+ T cell counts.
doi:10.1186/1742-6405-10-34
PMCID: PMC3904465  PMID: 24373482
HAART; Adherence; Herpes zoster; Incidence; Propensity score
17.  Non-communicable diseases in antiretroviral therapy recipients in Kagera Tanzania: a cross-sectional study 
Introduction
The aim of this study was to describe the extent of self-reported non-communicable diseases (NCDs) among highly active antiretroviral therapy (HAART) recipients in Kagera region in Tanzania and their effect on health-related quality of life (HRQOL). This study was conducted 2 years after HAART administration was started in Kagera region.
Methods
The SF-36 questionnaire was used to collect the HRQOL data of 329 HAART recipients. Questions on the NCDs, socio-demographic characteristics and treatment information were validated and added to the SF-36. Bivariate analyses involving socio-demographic characteristics and SF-36 scores of the recipients were performed. Multiple logistic regression was employed to compute adjusted odds ratios for different explanatory variables on physical functioning and mental health scores.
Results
Respondents who reported having 1 or more NCDs were 57.8% of all the respondents. Arthritis was the commonest NCD (57.8%). Respondents with the NCDs were more likely to have HRQOL scores below the mean of the general Tanzanian population. The population attributable fraction (PAF) for the NCDs on physical functioning was 0.28 and on mental health was 0.22.
Conclusion
Self-reported NCDs were prevalent among the HAART recipients in Kagera region. They accounted for 28% of the physical functioning scores and 22% of the mental health scores that were below the mean of the general Tanzanian population. Therefore, the integration of NCD care is important in the management of HIV/AIDS.
doi:10.11604/pamj.2013.16.84.2831
PMCID: PMC3976665
Non-communicable diseases; HIV/AIDS; highly active antiretroviral therapy; health-related quality of life; Tanzania
18.  Better quality of life with neuropsychological improvement on HAART 
Background
Successful highly active antiretroviral therapy (HAART) regimens have resulted in substantial improvements in the systemic health of HIV infected persons and increased survival times. Despite increased systemic health, the prevalence of minor HIV-associated cognitive impairment appears to be rising with increased longevity, and it remains to be seen what functional outcomes will result from these improvements. Cognitive impairment can dramatically impact functional ability and day-to-day productivity. We assessed the relationship of quality of life (QOL) and neuropsychological functioning with successful HAART treatment.
Methods
In a prospective longitudinal study, subjects were evaluated before instituting HAART (naïve) or before changing HAART regimens because current therapy failed to maintain suppression of plasma viral load (treatment failure). Subjects underwent detailed neuropsychological and neurological examinations, as well as psychological evaluation sensitive to possible confounds. Re-evaluation was performed six months after institution of the new HAART regimen and/or if plasma viral load indicated treatment failure. At each evaluation, subjects underwent ultrasensitive HIV RNA quantitative evaluation in both plasma and cerebrospinal fluid.
Results
HAART successes performed better than failures on measures exploring speed of mental processing (p < .02). HAART failure was significantly associated with increased self-reports of physical health complaints (p < .01) and substance abuse (p < .01). An interesting trend emerged, in which HAART failures endorsed greater levels of psychological and cognitive complaints (p = .06). Analysis between neuropsychological measures and QOL scores revealed significant correlation between QOL Total and processing speed (p < .05), as well as flexibility (p < .05).
Conclusion
Our study investigated the relationship between HIV-associated neurocognitive impairment and quality of life. HAART failures experienced slower psychomotor processing, and had increased self-reports of physical health complaints and substance abuse. Contrariwise, HAART successes experienced improved mental processing, demonstrating the impact of successful treatment on functioning. With increasing life expectancy for those who are HIV seropositive, it is important to measure cognitive functioning in relation to the actual QOL these individuals report. The study results have implications for the optimal management of HIV-infected persons. Specific support or intervention may be beneficial for those who have failed HAART in order to decrease substance abuse and increase overall physical health.
doi:10.1186/1477-7525-4-11
PMCID: PMC1397824  PMID: 16504114
19.  Severity of Lipodystrophy Is Associated with Decreased Health-Related Quality of Life 
AIDS Patient Care and STDs  2008;22(7):577-585.
Abstract
The impact of lipodystrophy (LD) on quality of life is high, but it has not been demonstrated in literature. The objective of the study was to assess the impact of LD on the health–related quality of life (HRQOL) in HIV-infected people on highly active antiretroviral therapy (HAART). Patients with LD phenotype defined by the Multicenter AIDS Cohort Study (MACS) were included. Three different methods were used to define LD severity: both patient and physician evaluation using the HIV Outpatient Study (HOPS) severity scales and the Lipodystrophy Case Definition (LDCD). The HRQOL was evaluated by MOS-HIV Health Survey. Four hundred one patients on HAART for a mean of 108 ± 52 months were evaluated for LD at the Metabolic Clinic of Modena and Reggio Emilia University were enrolled from January 2003 to July 2006. According to self-perceived or physician-based HOPS, 106 (26.5%) and 122 (30.4%) patients had severe LD. Females had significantly more severe LD. Few HRQOL scores correlated to LD severity using the physician-based score (both HOPSph and LDCD), while all the HRQOL scores correlated with LD severity when a patient-based score was used (HOPSpt). In multiple linear regression analysis, Mental Health HRQOL score, gender, body mass index, age, body image satisfaction were independent predictors of patient-based (HOPSpt) LD, while none of the HRQOL scores, but female gender, age, waist-to-hip ratio, limb fat, and body image satisfaction were correlated with physician-estimated HOPSph LD severity. HRQOL was strongly correlated with LD severity when a patient-based score was used. For an overall assessment of the impact of LD on HIV-infected people, both patient-based and physician-based measures are required.
doi:10.1089/apc.2007.0173
PMCID: PMC2929152  PMID: 18647097
20.  Tuberculosis treatment and risk of stavudine substitution in first line antiretroviral therapy 
Background
Treatment for tuberculosis (TB) is common among individuals receiving stavudine-containing highly active antiretroviral therapy (HAART), but the effect of TB treatment on stavudine toxicity has received little attention. We estimated the effect of TB treatment on risk of stavudine substitution among individuals receiving first-line HAART.
Methods
We evaluated a cohort of 7,066 patients who initiated HAART between April 2004 and March 2007 in Johannesburg, South Africa. Three exposure categories were considered: ongoing TB treatment at HAART initiation; concurrent initiation of TB treatment and HAART; incident TB treatment after HAART initiation. The outcome was single-drug stavudine substitution. Adjusted hazard ratios (aHRs) were estimated using marginal structural models to control for confounding, loss to follow-up, and competing risks.
Results
Individuals with ongoing and concurrent TB treatment were at increased risk of stavudine substitution, irrespective of stavudine dose. For ongoing TB treatment, aHR was 3.18 (95% confidence interval [CI] 1.82-5.56) in the first two months of HAART, 2.51 (95% CI 1.77-3.54) in months 3-6, and 1.19 (95% CI 0.94-1.52) thereafter. For concurrent TB treatment, aHR was 6.60 (95% CI 3.03-14.37) in the first two months,1.88 (95% CI 0.87-4.09) in months 3-6, and 1.07 (95% CI 0.65-1.76) thereafter. There was no effect of incident TB on stavudine substitution risk.
Conclusions
Risk of stavudine substitution was increased among patients receiving TB treatment, especially soon after HAART initiation. In settings where alternative antiretroviral drugs are available, initiation of stavudine in patients receiving TB treatment may need to be reconsidered.
doi:10.1086/598977
PMCID: PMC2787193  PMID: 19385733
Tuberculosis treatment; HIV; stavudine; highly active antiretroviral therapy (HAART); drug interactions
21.  Socio-economic, behavioural, (neuro)psychological and clinical determinants of HRQoL in people living with HIV in Belgium: a pilot study 
Introduction
Due to highly active antiretroviral therapy (HAART), HIV-1 infection has evolved from a lethal to a chronic disease. As such, health-related quality of life (HRQoL) has become an important outcome variable. The purpose of this study was to identify socio-economic, behavioural, (neuro)psychological and clinical determinants of HRQoL among people living with HIV (PLHIV).
Methods
This study was conducted between 1 January and 31 December 2012 at the AIDS Reference Centre of Ghent University Hospital, a tertiary care referral centre in Belgium. Validated self-report questionnaires were administered to collect socio-demographic data, to assess HRQoL (Medical Outcomes Study-HIV), depressive symptoms (Beck Depression Inventory-II) and adherence to HAART (Short Medication Adherence Questionnaire) and to screen for neurocognitive dysfunction.
Results
A total of 237 people participated, among whom 187 (78.9%) were male. Mean age was 45.8±10.7 years and 144 (63.7%, 144/226) participants were homosexual. Median physical and mental health score (PHS, MHS) were 55.6 (IQR 48.2–60.6) and 52.0 (IQR 44.2–57.9), respectively. Multivariable regression analysis revealed that incapacity to work, depressive symptoms, neurocognitive complaints (NCCs), dissatisfaction with the patient–physician relationship and non-adherence were all negatively associated with HRQoL.
Conclusions
Socio-economic (work status), behavioural (adherence) and (neuro)psychological (depressive symptoms, NCCs) determinants independently impact HRQoL among this cohort of PLHIV. Clinical parameters (viral load, CD4 cell count) were not independently associated with HRQoL.
doi:10.7448/IAS.16.1.18643
PMCID: PMC3862978  PMID: 24331754
HIV; AIDS; quality of life; MOS-HIV; psychosocial; outcome
22.  HIV and tuberculosis coinfection: inextricably linked liaison. 
In sub-Saharan Africa, human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (TB) are among the leading causes of morbidity and mortality. Sub-Saharan Africa has seen the woeful failure of World Health Organization (WHO) targets of detecting 70% of the infectious cases of tuberculosis and curing > or =85%. Current treatment of Mycobacterium tuberculosis in most resource limited settings is comprised of a four-drug initial antituberculosis regimen for two months, followed by either a two-drug continuation phase of antituberculosis regimen for four months or six months depending on the medications. Many countries in sub-Saharan Africa are scaling up with highly active antiretroviral therapy (HAART), using one of the first-line regimens that consist of two nucleoside reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Our current HAART regimen and antituberculosis drugs continue to give us a therapeutic challenge in terms of adverse effects, drug-drug interactions and immune reconstitution inflammatory syndromes. Scientific research is needed in the areas of diagnosis, treatment and prevention of tuberculosis in sub-Saharan Africa. Such research could be facilitated due to greater availability of funding than a decade ago.
PMCID: PMC2575925  PMID: 18229780
23.  Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda 
Neurology  2009;72(2):165-170.
Background:
The frequency of HIV dementia in a recent study of HIV+ individuals at the Infectious Disease Institute in Kampala, Uganda, was 31%. Coformulated generic drugs, which include stavudine, are the most common regimens to treat HIV infection in Uganda and many other parts of Africa.
Objective:
To evaluate the benefits and risks of stavudine-based highly active antiretroviral therapy (HAART) for HIV-associated cognitive impairment and distal sensory neuropathy. The study compared neuropsychological performance changes in HIV+ individuals initiating HAART for 6 months and HIV− individuals receiving no treatment for 6 months. The risk of antiretroviral toxic neuropathy as a result of the initiation of stavudine-based HAART was also examined.
Methods:
At baseline, 102 HIV+ individuals in Uganda received neurologic, neuropsychological, and functional assessments; began HAART; and were followed up for 6 months. Twenty-five HIV− individuals received identical clinical assessments and were followed up for 6 months.
Results:
In HIV+ individuals, there was improvement in verbal memory, motor and psychomotor speed, executive thinking, and verbal fluency. After adjusting for differences in sex, HIV+ individuals demonstrated significant improvement in the Color Trails 2 test (p = 0.025) compared with HIV− individuals. Symptoms of neuropathy developed in 38% of previously asymptomatic HIV+ patients after initiation of the stavudine-based HAART.
Conclusions:
After the initiation of highly active antiretroviral therapy (HAART) including stavudine, HIV+ individuals with cognitive impairment improve significantly as demonstrated by improved performance on a test of executive function. However, peripheral neurotoxicity occurred in 30 patients, presumably because of stavudine-based HAART, suggesting the need for less toxic therapy.
GLOSSARY
= Auditory Verbal Learning Test;
= Center for Epidemiologic Studies–Depression Scale;
= dideoxynucleoside antiretroviral drug;
= generalized estimating equation;
= Grooved Pegboard test;
= highly active antiretroviral therapy;
= HIV-associated sensory neuropathy;
= International HIV Dementia Scale;
= Memorial Sloan-Kettering;
= not applicable;
= not significant;
= Symbol Digit Modalities Test;
= University of California-Los Angeles;
= World Health Organization.
doi:10.1212/01.wnl.0000339042.96109.86
PMCID: PMC2677497  PMID: 19139369
24.  Drug Resistance and Viral Tropism in HIV-1 Subtype C-Infected Patients in KwaZulu-Natal, South Africa: Implications for Future Treatment Options 
Background
Drug resistance poses a significant challenge for the successful application of highly active antiretroviral therapy (HAART) globally. Furthermore, emergence of HIV-1 isolates that preferentially utilize CXCR4 as a coreceptor for cell entry, either as a consequence of natural viral evolution or HAART use may compromise the efficacy of CCR5 antagonists as alternative antiviral therapy.
Methods
We sequenced the pol gene of viruses from 45 individuals failing at least six months of HAART in Durban, South Africa to determine the prevalence and patterns of drug resistance mutations. Coreceptor usage profiles of these viruses and those from 45 HAART-naive individuals were analyzed using phenotypic and genotypic approaches.
Results
Ninety-five percent of HAART-failing patients had at least one drug resistance mutation. Thymidine analog mutations (TAMs) were present in 55% of patients with 9% of individuals possessing mutations indicative of the TAM1 pathway, 44% had TAM2 while 7% had mutations common to both pathways. Sixty percent of HAART-failing subjects had X4/dual//mixed-tropic viruses compared to 30% of HAART-naïve subjects (p<0.02). Genetic coreceptor usage prediction algorithms correlated with phenotypic results with 60% of samples from HAART-failing subjects predicted to possess CXCR4-using (X4/dual/mixed viruses) versus 15% of HAART-naïve patients.
Conclusions
The high proportion of TAMs and X4/dual/mixed HIV-1 viruses among patients failing therapy highlight the need for intensified monitoring of patients taking HAART and the problem of diminished drug options (including CCR5 antagonists) for patients failing therapy in resource-poor settings.
doi:10.1097/QAI.0b013e318228667f
PMCID: PMC3196677  PMID: 21709569
Coreceptor usage; viral tropism; antiretroviral drug resistance; HAART-failing patients; HAART-naïve patients
25.  A Randomized Controlled Trial Comparing the Effects of Counseling and Alarm Device on HAART Adherence and Virologic Outcomes 
PLoS Medicine  2011;8(3):e1000422.
Michael Chung and colleagues show that intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure, whereas use of an alarm device had no effect.
Background
Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting.
Methods and Findings
A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naïve individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.49–1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA ≥5,000 copies/ml) (HR 0.41; 95% CI 0.21–0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65–1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53–1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution.
Conclusions
Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.
Trial registration
ClinicalTrials gov NCT00273780
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Adherence to HIV treatment programs in poor countries has long been cited as an important public health concern, especially as poor adherence can lead to drug resistance and inadequate treatment of HIV. However, two factors have recently cast doubt on the poor adherence problem: (1) recent studies have shown that adherence is high in African HIV treatment programs and often better than in Western HIV clinics. For example, in a meta-analysis of 27 cohorts from 12 African countries, adequate adherence was noted in 77% of subjects compared to only 55% among 31 North America cohorts; (2) choice of antiretroviral regimens may impact on the development of antiretroviral resistance. In poor countries, most antiretroviral regimens contain non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine or efavirenz, which remain in the patient's circulation for weeks after single-dose administration. This situation means that such patients may not experience antiretroviral resistance unless they drop below 80% adherence—contrary to the more stringent 95% plus adherence levels needed to prevent resistance in regimens based on unboosted protease inhibitors—ultimately, off-setting some treatment lapses in resource-limited settings where NNRTI-based regimens are widely used.
Why Was This Study Done?
Given that adherence may not be as crucial an issue as previously thought, antiretroviral treatment programs in sub-Saharan Africa may be spending scarce resources to promote adherence to the detriment of some potentially more effective elements of HIV treatment and management programs. Although many treatment programs currently include adherence interventions, there is limited quality evidence that any of these methods improve long-term adherence to HIV treatment. Therefore, it is necessary to identify adherence interventions that are inexpensive and proven to be effective in resource-limited settings. As adherence counseling is already widely implemented in African HIV treatment programs and inexpensive alarm devices are thought to also improve compliance, the researchers compared the impact of adherence counseling and the use of an alarm device on adherence and biological outcomes in patients enrolled in HIV programs in rural Kenya.
What Did the Researchers Do and Find?
The researchers enrolled 400 eligible patients (newly diagnosed with HIV, never before taken antiretroviral therapy, aged over 18 years) to four arms: (1) adherence counseling alone; (2) alarm device alone; (3) both adherence counseling and alarm device together; and (4) a control group that received neither adherence counseling nor alarm device. The patients had blood taken to record baseline CD4 count and HIV-1 RNA and after starting HIV treatment, returned to the study clinic every month with their pill bottles for the study pharmacist to count and recorded the number of pills remaining in the bottle, and to receive another prescription. Patients were followed up for 18 months and had their CD4 count and HIV-1 RNA measured at 6, 12, and 18 months.
Patients receiving adherence counseling were 29% less likely to experience poor adherence compared to those who received no counseling. Furthermore, those receiving intensive early adherence counseling were 59% less likely to experience viral failure. However, there was no significant difference in mortality or significant differences in CD4 counts at 18 months follow-up between those who received counseling and those who did not. There were no significant differences in adherence, time to viral failure, mortality, or CD4 counts in patients who received alarm devices compared to those who did not.
What Do These Findings Mean?
The results of this study suggest that intensive adherence counseling around the time of HIV treatment initiation significantly reduces poor adherence and virologic treatment failure, while using an alarm device has no effect. Therefore, investment in careful counseling based on individual needs at the onset of HIV treatment initiation, appears to have sustained benefit, possibly through strengthening the relationship between the health care provider and patient through communication, education, and trust. Interactive adherence counseling supports the bond between the clinic and the patient and may result in fewer patients needing to switch to expensive second-line medications and, possibly, may help to decrease the spread of resistant HIV. These findings define an adherence counseling protocol that is effective and are highly relevant to other HIV clinics caring for large numbers of patients in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000422.
UNAIDS provides information about HIV treatment strategies
The American Public Health Association has information about adherence to HIV treatment regimens
The US Department of Health and Human Services has information for patients about adherence to HIV treatment
The World Health Organization provides information about HIV treatment pharmacovigilance
doi:10.1371/journal.pmed.1000422
PMCID: PMC3046986  PMID: 21390262

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