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1.  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
2.  Antiretroviral Treatment and Prevention of Peripartum and Postnatal HIV Transmission in West Africa: Evaluation of a Two-Tiered Approach 
PLoS Medicine  2007;4(8):e257.
Background
Highly active antiretroviral treatment (HAART) has only been recently recommended for HIV-infected pregnant women requiring treatment for their own health in resource-limited settings. However, there are few documented experiences from African countries. We evaluated the short-term (4 wk) and long-term (12 mo) effectiveness of a two-tiered strategy of prevention of mother-to-child transmission of HIV (PMTCT) in Africa: women meeting the eligibility criteria of the World Health Organization (WHO) received HAART, and women with less advanced HIV disease received short-course antiretroviral (scARV) PMTCT regimens.
Methods and Findings
The MTCT-Plus Initiative is a multi-country, family-centred HIV care and treatment program for pregnant and postpartum women and their families. Pregnant women enrolled in Abidjan, Côte d'Ivoire received either HAART for their own health or short-course antiretroviral (scARV) PMTCT regimens according to their clinical and immunological status. Plasma HIV-RNA viral load (VL) was measured to diagnose peripartum infection when infants were 4 wk of age, and HIV final status was documented either by rapid antibody testing when infants were aged ≥ 12 mo or by plasma VL earlier. The Kaplan-Meier method was used to estimate the rate of HIV transmission and HIV-free survival. Between August 2003 and June 2005, 107 women began HAART at a median of 30 wk of gestation, 102 of them with zidovudine (ZDV), lamivudine (3TC), and nevirapine (NVP) and they continued treatment postpartum; 143 other women received scARV for PMTCT, 103 of them with sc(ZDV+3TC) with single-dose NVP during labour. Most (75%) of the infants were breast-fed for a median of 5 mo. Overall, the rate of peripartum HIV transmission was 2.2% (95% confidence interval [CI] 0.3%–4.2%) and the cumulative rate at 12 mo was 5.7% (95% CI 2.5%–9.0%). The overall probability of infant death or infection with HIV was 4.3% (95% CI 1.7%–7.0%) at age week 4 wk and 11.7% (95% CI 7.5%–15.9%) at 12 mo.
Conclusions
This two-tiered strategy appears to be safe and highly effective for short- and long-term PMTCT in resource-constrained settings. These results indicate a further benefit of access to HAART for pregnant women who need treatment for their own health.
In an observational cohort study from Côte d'Ivoire, François Dabis and colleagues report on prevention of mother-to-child HIV transmission among women receiving antiretroviral therapy according to World Health Organization recommendations.
Editors' Summary
Background
Effective treatments are available to prevent AIDS in people who are infected with HIV, but not everyone with HIV needs to take medication. Usually, anti-HIV medication is recommended only for those whose immune systems have been significantly affected by the virus, as evidenced by symptoms or by the results of a blood test, the CD4 lymphocyte (“T cell”) count. Treating HIV usually requires a combination of three or more medications. These combinations (called HAART) must be taken every day, can cause complications, and can be expensive.
Worldwide, more than half a million children became infected with HIV each year. Most of these children acquire HIV from their mothers during pregnancy or around the time of birth. If a pregnant woman with HIV takes HAART, her chances of passing HIV to the baby are greatly reduced, but the possible side effects of HAART on the baby are not known. Also, most transmission of HIV from mothers to babies occurs in poor countries where supplies of HAART are limited. For these reasons, World Health Organization (WHO) does not recommend that every pregnant woman receive HAART to prevent HIV transmission to the baby, unless the woman needs HAART for her own health (for example if her T cells are low or she has severe symptoms of HIV infection). For pregnant women with HIV who do not need to take HAART for their own health, less complicated treatments, involving a short course of one or two HIV drugs, can be used to reduce the risk of passing HIV to the baby.
Why Was This Study Done?
The WHO recommendations for HAART in pregnancy are based on the best available evidence, but it is important to know how well they work in actual practice. The authors of this study were providing HIV treatment to pregnant women with HIV in West Africa through an established clinic program in Abidjan, Côte d'Ivoire, and wanted to see how well the WHO recommendations for HAART or short-course treatments, depending on the mother's condition, were working to protect babies from HIV infection.
What Did the Researchers Do and Find?
The researchers studied 250 HIV-infected pregnant women who received HIV medications in the Abidjan program between mid-2003 and mid-2005. In accordance with WHO guidelines, 107 women began HAART for their own health during pregnancy, and 143 women did not qualify for HAART but received other short course treatments (scARV) to prevent HIV transmission to their babies. The authors monitored mothers and babies for treatment side effects and tested the babies for HIV infection up to age 1 y.
They found that HAART was relatively safe during pregnancy, although babies born to women on HAART were more likely (26.3%) to have low birth weight than babies born to women who received scARV (12.4%). Also, 7.5% of women on HAART developed side effects requiring a change in their medications. Combining the results from HAART and scART groups, the chance of HIV transmission around the time of birth was 2.2%, increasing to 5.7% at age 1 y. (Three-quarters of the infants were breast-fed; safe water for mixing formula was not reliably available.) The study found no difference in risk of HIV infection between babies whose mothers received HAART and those whose mothers received scARV according to guidelines.
What Do These Findings Mean?
These results support the safety and effectiveness of the WHO two-tiered approach for preventing mother-to-child transmission. This study was not designed to compare HAART to scART directly, because the women who received HAART were the ones with more advanced HIV infection, which might have affected their babies in many ways.
Compared to earlier pregnancy studies of HAART in rich countries, this study of the WHO approach in West Africa showed similar success in protecting infants from HIV infection around the time of birth. Unfortunately, because formula feeding was not generally available in resource-limited settings, protection declined over the first year of life with breast-feeding, but some protection remained.
This study confirms that close monitoring of pregnant women on HAART is necessary, so that drugs can be changed if side effects develop. The study does not tell us whether using scARV in pregnancy might change the virus in ways that would make it more difficult to treat the same women with HAART later if they needed it. The reason for low birth weight in some babies born to mothers on HAART is unclear. It may be because the women who needed HAART had more severe health problems from their HIV, or it may be a result of the HAART itself.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040257.
World Health Organization has a page on prevention of mother-to-child transmission of HIV
“Women, Children, and HIV” is a resource site from the François Xavier Bagnoud Center and UCSF
The MTCT-Plus initiative at Columbia University supports the programs in Abidjan
doi:10.1371/journal.pmed.0040257
PMCID: PMC1949842  PMID: 17713983
3.  Assessment of quality of life in HAART-treated HIV-positive subjects with body fat redistribution in Rwanda 
Background
The introduction of HAART has initially improved the quality of life (QoL) of HIV-positive (HIV+) patients, however body fat redistribution (BFR) and metabolic disorders associated with long-term HAART use may attenuate this improvement. As access to treatment improves in sub-Saharan Africa, the disfiguring nature of BFR (peripheral atrophy and/or central adiposity) may deter treatment adherence and initiatives and decrease QoL. We examined the relationship between BFR and domains of QoL in HAART-treated HIV+ African men and women with (HIV+BFR, n = 50) and without (HIV+noBFR, n = 50) BFR in Rwanda.
Results
HIV+ subjects with BFR were less satisfied with their body image (4.3 ± 0.1 versus 1.5 ± 0.2; p < .001), self-esteem and social life (4.1 ± 1.4 versus 2.1 ± 0.3; p = 0.003). HIV+BFR were more ashamed in public (4.5 ± 1.2 versus 1.1 ± 1.1), reported less confident about their health (4.6 ± 1.4 versus 1.5 ± 1.2) and were frequently embarrassed due to body changes (4.1 ± 1.1 versus 1.1 ± 0.9) (p < .001) than HIV+noBFR. HIV+ Rwandan women with BFR reported more dissatisfaction with psychological (8.3 ± 2.9 versus 13.7 ± 1.9), social relationships (6.9 ± 2.3 versus 11.1 ± 4.1) and HIV HAART-specific domain of wellbeing (3.1 ± 4.8 versus 6.3 ± 3.6) (p < .001). Age was associated with independence (r2 = 0.691; p = 0.009) and marital status was associated with psychological (r2 = 0.593; p = 0.019) and social relationships (r2 = 0.493; p = 0.007). CD4 count (r2 = 0.648; p = 0.003) and treatment duration (r2 = 0.453; p = 0.003) were associated with HIV HAART-specific domain of wellbeing. HIV+ Rwandan women with BFR were significantly more affected by abdominal adiposity (p < .001), facial and buttocks atrophy (p < .05) than HIV+ men with BFR.
Conclusion
Body fat alterations negatively affect psychological and social domains of quality of life. These symptoms may result in stigmatization and marginalization mainly in HAART-treated African women, adversely affecting HAART adherence and treatment initiatives. Efforts to evaluate self-perceived body fat changes may improve patients' wellbeing, HAART adherence and treatment outcomes and contribute towards stability in quality of life continuum.
doi:10.1186/1742-6405-4-19
PMCID: PMC2075499  PMID: 17877798
4.  The Association of Self-perception of Body Fat Changes and Quality of Life in the Women’s Interagency HIV Study 
AIDS care  2013;25(12):10.1080/09540121.2013.793265.
Body fat changes are of concern to HIV-seropositive adults on highly active antiretroviral therapy (HAART). Studies examining the association of body fat changes and quality of life (QOL) in the setting of HIV infection have been conducted predominately in men. We examined the relationship of self-perceived body fat change with QOL among 1,671 HAART-using HIV-seropositive women (mean age 40 ± 8 years; 54% African American, 24% reporting ≤ 95% HAART adherence) from the Women’s Interagency HIV Study. Self-perception of any fat loss was associated with lower overall QOL. Report of any peripheral fat loss was strongly associated with nearly all QOL domains (i.e., physical functioning, role functioning, energy/fatigue, social functioning, pain, emotional well-being, health perception, and perceived health index) except cognitive functioning, whereas report of any central fat loss was significantly associated with lower social and cognitive functioning. Report of any central fat gain was associated with lower overall QOL, but only physical functioning, energy/fatigue, and cognitive functioning were significantly affected. A significant association of report of any peripheral fat gain with overall QOL was not observed, however peripheral fat gain was significantly associated with lower physical functioning and pain. We found that any report of fat loss, especially in peripheral body sites is associated with lower QOL, as was any report of central fat gain. Ultimately health providers and patients need to be informed of these associations so as to better support HIV-seropositive women who live with these effects.
doi:10.1080/09540121.2013.793265
PMCID: PMC3769511  PMID: 23656440
body image perception; lipoatrophy; lipohypertrophy; Quality of life; HIV-seropositive women; HAART
5.  Injection drug use and patterns of highly active antiretroviral therapy use: an analysis of ALIVE, WIHS, and MACS cohorts 
Background
Sustained use of antiretroviral therapy has been consistently shown to be one of the primary predictors of long-term effectiveness. Switching and discontinuation reflect patient and provider decisions that may limit future treatment options. In this study, we utilize data reported at semi-annual study visits from three prospective cohort studies, the AIDS Link to IntraVenous Exposure (ALIVE), the Women's Interagency HIV Study (WIHS), and the Multicenter AIDS Cohort Study (MACS), to investigate determinants of HAART modification with a particular focus on reported injection drug use (IDU).
Methods
Longitudinal data collected between 1996 and 2004 contributed from 2,266 participants (37% with a reported history of IDU) who reported initiating their first HAART regimen during follow-up were utilized. Separate proportional-hazards models were used to identify factors measured prior to HAART-initiation associated with the time to first HAART discontinuation and first switch of components of HAART among continuous HAART users.
Results
The use of PI- vs. NNRTI-based regimens among HAART users with and without any history of IDU was similar over follow-up. The median time to a first report of discontinuation of HAART was 1.1 years for individuals with a history of IDU but 2.5 years for those without a history of IDU and multivariate analyses confirmed overall that individuals with a history of IDU were at greater risk for HAART discontinuation (adj RH = 1.24, 95% CI: 1.03–1.48). However, when restricting to data contributed after 1999, there was no longer any significant increased risk (adj RH = 1.05, 95% CI: 0.81–1.36). After adjusting for pre-HAART health status and prior ARV exposure, individuals who were ethnic/racial minorities, reported an annual income < $10,000/year, and were not employed were at significantly greater risk for HAART discontinuation. The median time to a first change in HAART regimen was approximately 1.5 years after first HAART report and was not elevated among those with a history of IDU (adj RH = 1.09, 95% CI: 0.89–1.34).
Conclusion
Our analyses demonstrate that injection drug use by itself does not appear to be an independent risk factor for HAART switching or discontinuation in more recent years. However, as continued HAART use is of paramount importance for long-term control of HIV infection, efforts to improve maintenance to therapy among disadvantaged and minority populations remain greatly needed.
doi:10.1186/1742-6405-4-12
PMCID: PMC1892565  PMID: 17553140
6.  Emergence of Drug Resistance Is Associated with an Increased Risk of Death among Patients First Starting HAART 
PLoS Medicine  2006;3(9):e356.
Background
The impact of the emergence of drug-resistance mutations on mortality is not well characterized in antiretroviral-naïve patients first starting highly active antiretroviral therapy (HAART). Patients may be able to sustain immunologic function with resistant virus, and there is limited evidence that reduced sensitivity to antiretrovirals leads to rapid disease progression or death. We undertook the present analysis to characterize the determinants of mortality in a prospective cohort study with a median of nearly 5 y of follow-up. The objective of this study was to determine the impact of the emergence of drug-resistance mutations on survival among persons initiating HAART.
Methods and Findings
Participants were antiretroviral therapy naïve at entry and initiated triple combination antiretroviral therapy between August 1, 1996, and September 30, 1999. Marginal structural modeling was used to address potential confounding between time-dependent variables in the Cox proportional hazard regression models. In this analysis resistance to any class of drug was considered as a binary time-dependent exposure to the risk of death, controlling for the effect of other time-dependent confounders. We also considered each separate class of mutation as a binary time-dependent exposure, while controlling for the presence/absence of other mutations. A total of 207 deaths were identified among 1,138 participants over the follow-up period, with an all cause mortality rate of 18.2%. Among the 679 patients with HIV-drug-resistance genotyping done before initiating HAART, HIV-drug resistance to any class was observed in 53 (7.8%) of the patients. During follow-up, HIV-drug resistance to any class was observed in 302 (26.5%) participants. Emergence of any resistance was associated with mortality (hazard ratio: 1.75 [95% confidence interval: 1.27, 2.43]). When we considered each class of resistance separately, persons who exhibited resistance to non-nucleoside reverse transcriptase inhibitors had the highest risk: mortality rates were 3.02 times higher (95% confidence interval: 1.99, 4.57) for these patients than for those who did not exhibit this type of resistance.
Conclusions
We demonstrated that emergence of resistance to non-nucleoside reverse transcriptase inhibitors was associated with a greater risk of subsequent death than was emergence of protease inhibitor resistance. Future research is needed to identify the particular subpopulations of men and women at greatest risk and to elucidate the impact of resistance over a longer follow-up period.
Emergence of resistance to both non-nucleoside reverse transcriptase inhibitors and protease inhibitors was associated with a higher risk of subsequent death, but the risk was greater in patients with NNRTI-resistant HIV.
Editors' Summary
Background.
In the 1980s, infection with the human immunodeficiency virus (HIV) was effectively a death sentence. HIV causes AIDS (acquired immunodeficiency syndrome) by replicating inside immune system cells and destroying them, which leaves infected individuals unable to fight off other viruses and bacteria. The first antiretroviral drugs were developed quickly, but it soon became clear that single antiretrovirals only transiently suppress HIV infection. HIV mutates (accumulates random changes to its genetic material) very rapidly and, although most of these changes (or mutations) are bad for the virus, by chance some make it drug resistant. Highly active antiretroviral therapy (HAART), which was introduced in the mid-1990s, combines three or four antiretroviral drugs that act at different stages of the viral life cycle. For example, they inhibit the reverse transcriptase that the virus uses to replicate its genetic material, or the protease that is necessary to assemble new viruses. With HAART, the replication of any virus that develops resistance to one drug is inhibited by the other drugs in the mix. As a consequence, for many individuals with access to HAART, AIDS has become a chronic rather than a fatal disease. However, being on HAART requires patients to take several pills a day at specific times. In addition, the drugs in the HAART regimens often have side effects.
Why Was This Study Done?
Drug resistance still develops even with HAART, often because patients don't stick to the complicated regimens. The detection of resistance to one drug is usually the prompt to change a patient's drug regimen to head off possible treatment failure. Although most patients treated with HAART live for many years, some still die from AIDS. We don't know much about how the emergence of drug-resistance mutations affects mortality in patients who are starting antiretroviral therapy for the first time. In this study, the researchers looked at how the emergence of drug resistance affected survival in a group of HIV/AIDS patients in British Columbia, Canada. Here, everyone with HIV/AIDS has access to free medical attention, HAART, and laboratory monitoring, and full details of all HAART recipients are entered into a central reporting system.
What Did the Researchers Do and Find?
The researchers enrolled people who started antiretroviral therapy for the first time between August 1996 and September 1999 into the HAART Observational Medical Evaluation and Research (HOMER) cohort. They then excluded anyone who was infected with already drug-resistant HIV strains (based on the presence of drug-resistance mutations in viruses isolated from the patients) at the start of therapy. The remaining 1,138 patients were followed for an average of five years. All the patients received either two nucleoside reverse transcriptase inhibitors and a protease inhibitor, or two nucleoside and one non-nucleoside reverse transcriptase inhibitor (NNRTI). Nearly a fifth of the study participants died during the follow-up period. Most of these patients actually had drug-sensitive viruses, possibly because they had neglected taking their drugs to such an extent that there had been insufficient drug exposure to select for drug-resistant viruses. In a quarter of the patients, however, HIV strains resistant to one or more antiretroviral drugs emerged during the study (again judged by looking for mutations). Detailed statistical analyses indicated that the emergence of any drug resistance nearly doubled the risk of patients dying, and that people carrying viruses resistant to NNRTIs were three times as likely to die as those without resistance to this class of antiretroviral drug.
What Do These Findings Mean?
These results provide new information about the emergence of drug-resistant HIV during HAART and possible effects on the long-term survival of patients. In particular, they suggest that clinicians should watch carefully for the emergence of resistance to NNRTIs in their patients. Because this type of resistance is often due to poor adherence to drug regimens, these results also suggest that increased efforts should be made to ensure that patients comply with the prescribed HAART regimens, especially those whose antiretroviral therapy includes NNRTIs. As with all studies in which a group of individuals who share a common characteristic are studied over time, it is possible that some other, unmeasured difference between the patients who died and those who didn't—rather than emerging drug resistance—is responsible for the observed differences in survival. Additional studies are needed to confirm the findings here, and to investigate whether specific subpopulations of patients are at particular risk of developing drug resistance and/or dying during HAART.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030356.
US National Institute of Allergy and Infectious Diseases fact sheet on HIV infection and AIDS
US Department of Health and Human Services information on AIDS, including details of approved drugs for the treatment of HIV infection
US Centers for Disease Control and Prevention information on HIV/AIDS
Aidsmap, information on HIV and AIDS provided by the charity NAM, which includes details on antiretroviral drugs
doi:10.1371/journal.pmed.0030356
PMCID: PMC1569883  PMID: 16984218
7.  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
8.  Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment 
Background
Inflammation and hemostasis perturbation may be involved in vascular complications of HIV infection. We examined atherogenic biomarkers and subclinical atherosclerosis in HIV-infected adults before and after beginning highly-active antiretroviral therapy (HAART).
Methods
In the Women's Interagency HIV Study (WIHS), 127 HIV-infected women studied pre- and post-HAART were matched to HIV-uninfected controls. Six semi-annual measurements of soluble CD14, tumor necrosis factor (TNF)-alpha, soluble interleukin (IL)-2 receptor, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, D-dimer, and fibrinogen were obtained. Carotid artery intima-media thickness (CIMT) was measured by B-mode ultrasound.
Results
Relative to HIV-uninfected controls, HAART-naïve HIV-infected women had elevated levels of soluble CD14 (1945 vs 1662 ng/mL, Wilcoxon signed rank P<0.0001), TNF-alpha (6.3 vs 3.4 pg/mL, P<0.0001), soluble IL-2 receptor (1587 vs 949 pg/mL, P<0.0001), IL-10 (3.3 vs 1.9 pg/mL, P<0.0001), MCP-1 (190 vs 163 pg/mL, P<0.0001) and D-dimer (0.43 vs 0.31 µg/mL, P<0.01). Elevated biomarker levels declined after HAART. While most biomarkers normalized to HIV-uninfected levels, in women on effective HAART, TNF-alpha levels remained elevated compared to HIV-uninfected women (+0.8 pg/mL, P=0.0002). Higher post-HAART levels of soluble IL-2 receptor (P=0.02), IL-6 (P=0.05), and D-dimer (P=0.03) were associated with increased CIMT.
Conclusions
Untreated HIV infection is associated with abnormal hemostasis (e.g., D-dimer), and pro-atherogenic (e.g., TNF-alpha) and anti-atherogenic (e.g., IL-10) inflammatory markers. HAART reduces most inflammatory mediators to HIV-uninfected levels. Increased inflammation and hemostasis are associated with subclinical atherosclerosis in recently treated women. These findings have potential implications for long-term risk of cardiovascular disease in HIV-infected patients, even with effective therapy.
doi:10.1097/QAI.0b013e31825b03be
PMCID: PMC3400505  PMID: 22592585
antiretroviral therapy; cardiovascular diseases; cytokines; hemostasis; HIV; inflammation
9.  Effects of long-term use of HAART on oral health status of HIV-infected subjects 
BACKGROUND
The aim of this study was to determine the effects of long-term use of highly active antiretroviral therapy (HAART) on oral health status of HIV-infected subjects.
METHODS
Oral examination and measurement of saliva flow rate of both unstimulated and wax-stimulated whole saliva were performed in HIV-infected subjects with and without HAART, and in non-HIV individuals. The following data were recorded; duration and risk of HIV infection, type and duration of HAART, CD4 cell count, viral load, presence of orofacial pain, oral dryness, oral burning sensation, oral lesions, cervical caries, and periodontal pocket. Multiple logistic regression analysis was performed to determine the effects of long-term use of HAART on oral health status of HIV-infected subjects. RESULTS: One hundred and fifty-seven HIV-infected subjects – 99 on HAART (age range 23–57 years, mean 39 years) and 58 not on HAART (age range 20–59 years, mean 34 years) – and 50 non-HIV controls (age range 19–59 years, mean 36 years) were enrolled. The most common HAART regimen was 2 NRTI + 2 NNRTI. HIV-infected subjects without HAART showed greater risks of having orofacial pain, oral dryness, oral lesions, and periodontal pockets than those with short-term HAART (P < 0.01). The subjects with long-term HAART were found to have a greater risk of having oral lesions than those with short-term HAART (P < 0.05). The unstimulated and stimulated salivary flow rates of the subjects with HAART were significantly lower than in those without HAART (P < 0.05).
CONCLUSION
We conclude that long-term HAART has adverse effects on oral health status of HIV-infected subjects.
doi:10.1111/j.1600-0714.2009.00875.x
PMCID: PMC3217232  PMID: 20202089
HAART; HIV; oral health; oral lesion; risk factor; salivary flow rate
10.  Inflammatory Biomarkers and Abacavir Use in the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(11):1657-1665.
Objective
To assess associations between abacavir (ABC) use and systemic inflammation.
Design
Retrospective case-control study.
Methods
MACS & WIHS cohort participants who initiated ABC were matched, using propensity score methods, to ABC-unexposed persons. Levels of hsCRP(μg/mL), IL-6(pg/mL), and D-dimer (μg/mL) were measured from pre-HAART and on-HAART plasma. Random-effects models compared markers by ABC exposure and by changes from pre-HAART levels.
Results
Biomarkers were measured in N=508 matched pairs (328 women; 180 men). Pre-HAART levels did not differ by exposure group except that hsCRP levels were higher among WIHS women who subsequently used ABC (p=0.04). Regardless of ABC use, mean hsCRP increases and D-dimer reductions were seen when comparing pre- to on-HAART levels, in the overall group (28% and -27%), for MACS men (28% and -31%) and for WIHS women (29% and -24% (p<0.01 for all); IL-6 levels declined in MACS men (p=0.02). No adjusted biomarker level differences existed by ABC exposure at the on-HAART visit. HIV RNA reductions correlated with D-dimer (r = 0.14, p < 0.01) and IL-6 (r = 0.12, p < 0.01) reductions. Associations between ABC use and mean biomarker levels were modified by pre-HAART ART experience. Renal dysfunction was equally likely among non-ABC and ABC recipients.
Discussion
ABC use was not associated with plasma elevations in hsCRP, IL-6 and d-dimer. Mechanisms other than increased systemic inflammation may account for ABC’s reported association with increased cardiovascular disease. HAART -associated reductions in D-dimer and IL-6 were apparent regardless of ABC use and were correlated with HIV RNA reductions.
doi:10.1097/QAD.0b013e3283389dfa
PMCID: PMC3514460  PMID: 20588104
HIV infection; inflammation; HAART; abacavir; cytokines
11.  Antiretroviral-Treated HIV-Infected Women Have Similar Long-Term Kidney Function Trajectories as HIV-Uninfected Women 
Abstract
Natural history studies suggest increased risk for kidney function decline with HIV infection, but few studies have made comparisons with HIV-uninfected women. We examined whether HIV infection treated with highly active antiretroviral therapy (HAART) remains associated with faster kidney function decline in the Women's Interagency HIV Study. HIV-infected women initiating HAART with (n=105) or without (n=373) tenofovir (TDF) were matched to HIV-uninfected women on calendar and length of follow-up, age, systolic blood pressure, hepatitis C antibody serostatus, and diabetes history. Linear mixed models were used to evaluate differences in annual estimated glomerular filtration rate (eGFR). Person-visits were 4,741 and 11,512 for the TDF-treated and non-TDF-treated analyses, respectively. Mean baseline eGFRs were higher among women initiated on TDF-containing HAART and lower among those on TDF-sparing HAART compared to their respective HIV-uninfected matches (p<0.05 for both). HIV-infected women had annual rates of eGFR changes similar to HIV-uninfected matches (p-interaction >0.05 for both). Adjusting for baseline eGFR, mean eGFRs at 1 and 3 years of follow-up among women initiated on TDF-containing HAART were lower than their uninfected matches (−4.98 and −4.26 ml/min/1.73 m2, respectively; p<0.05 for both). Mean eGFR of women initiated on TDF-sparing HAART was lower versus uninfected matches at 5 years (–2.19 ml/min/1.73 m2, p=0.03). HAART-treated HIV-infected women had lower mean eGFRs at follow-up but experienced rates of annual eGFR decline similar to HIV-uninfected women. Tenofovir use in HIV-infected women with normal kidney function did not accelerate long-term kidney function decline relative to HIV-uninfected women.
doi:10.1089/aid.2012.0248
PMCID: PMC3636577  PMID: 23273313
12.  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
13.  Short-term Garlic Supplementation and Highly Active Antiretroviral Treatment Adherence, CD4+ Cell Counts, and Human Immunodeficiency Virus Viral Load 
Context
Human immunodeficiency virus (HIV)–infected individuals frequently have consumed garlic, a popular complementary supplement. Researchers rarely have studied garlic’s association with antiretroviral therapies, however, even though that association is very relevant clinically.
Objective
To examine associations of supplemental use of garlic with highly active antiretroviral treatment (HAART) adherence level and HAART effectiveness (HIV viral load and CD4+ cell counts) in HIV-infected women.
Design
The research team carried out a self-controlled, longitudinal study nested within the Women’s Interagency HIV Study (WIHS). The team used a paired study design that allowed participants to serve as their own controls. The team first identified all of the study’s visits in which the participant self-reported the use of a garlic supplement since her last visit (index visit). Then for each index visit, the team identified a matching visit (a control visit) using the following criteria: (a) the visit must be one for the same participant in which that participant reported no garlic supplementation; (b) the visit must immediately precede the index visit (less than 1 year apart); and (c) at the time of the control visit, the participant must have been using antiretroviral therapy identical to that used at the time of the index visit.
Participants
Participants were persons using garlic supplementation who already were participants in the WIHS.
Outcome Measures
The research team used a logistic regression model to examine the association between garlic supplementation and HAART adherence level. The team used a mixed linear model to examine the association of garlic supplementation with HIV viral load and CD4+ cell counts.
Results
From October 1994 to April 2009, 390 HIV-infected women in the WIHS made 1112 visits at which they reported using garlic supplements. Seventy-seven HIV-infected women using HAART met the research team’s selection criteria and contributed 99 pairs of visits for the study. Among the women who used garlic supplements, 22% were 50 years and older; 58% were black and non-Hispanic; and 23% had less than a high-school education. Neither use of garlic supplementation nor reasons for using garlic supplements were significantly associated with the HAART adherence level, HIV viral load, or CD4+ cell counts; however, “use garlic as needed,” a potential marker of a disease state, was significantly associated with higher viral load (P = .0003).
Conclusion
Short-term garlic supplementation did not impact HAART adherence level, HIV viral load, and CD4+ cell counts.
PMCID: PMC3376904  PMID: 22516847
14.  Antiretroviral Therapy Initiation Before, During, or After Pregnancy in HIV-1-Infected Women: Maternal Virologic, Immunologic, and Clinical Response 
PLoS ONE  2009;4(9):e6961.
Background
Pregnancy has been associated with a decreased risk of HIV disease progression in the highly active antiretroviral therapy (HAART) era. The effect of timing of HAART initiation relative to pregnancy on maternal virologic, immunologic and clinical outcomes has not been assessed.
Methods
We conducted a retrospective cohort study from 1997–2005 among 112 pregnant HIV-infected women who started HAART before (N = 12), during (N = 70) or after pregnancy (N = 30).
Results
Women initiating HAART before pregnancy had lower CD4+ nadir and higher baseline HIV-1 RNA. Women initiating HAART after pregnancy were more likely to receive triple-nucleoside reverse transcriptase inhibitors. Multivariable analyses adjusted for baseline CD4+ lymphocytes, baseline HIV-1 RNA, age, race, CD4+ lymphocyte count nadir, history of ADE, prior use of non-HAART ART, type of HAART regimen, prior pregnancies, and date of HAART start. In these models, women initiating HAART during pregnancy had better 6-month HIV-1 RNA and CD4+ changes than those initiating HAART after pregnancy (−0.35 vs. 0.10 log10 copies/mL, P = 0.03 and 183.8 vs. −70.8 cells/mm3, P = 0.03, respectively) but similar to those initiating HAART before pregnancy (−0.32 log10 copies/mL, P = 0.96 and 155.8 cells/mm3, P = 0.81, respectively). There were 3 (25%) AIDS-defining events or deaths in women initiating HAART before pregnancy, 3 (4%) in those initiating HAART during pregnancy, and 5 (17%) in those initiating after pregnancy (P = 0.01). There were no statistical differences in rates of HIV disease progression between groups.
Conclusions
HAART initiation during pregnancy was associated with better immunologic and virologic responses than initiation after pregnancy.
doi:10.1371/journal.pone.0006961
PMCID: PMC2734183  PMID: 19742315
15.  Evolution of Antiretroviral Drug Costs in Brazil in the Context of Free and Universal Access to AIDS Treatment  
PLoS Medicine  2007;4(11):e305.
Background
Little is known about the long-term drug costs associated with treating AIDS in developing countries. Brazil's AIDS treatment program has been cited widely as the developing world's largest and most successful AIDS treatment program. The program guarantees free access to highly active antiretroviral therapy (HAART) for all people living with HIV/AIDS in need of treatment. Brazil produces non-patented generic antiretroviral drugs (ARVs), procures many patented ARVs with negotiated price reductions, and recently issued a compulsory license to import one patented ARV. In this study, we investigate the drivers of recent ARV cost trends in Brazil through analysis of drug-specific prices and expenditures between 2001 and 2005.
Methods and Findings
We compared Brazil's ARV prices to those in other low- and middle-income countries. We analyzed trends in drug expenditures for HAART in Brazil from 2001 to 2005 on the basis of cost data disaggregated by each ARV purchased by the Brazilian program. We decomposed the overall changes in expenditures to compare the relative impacts of changes in drug prices and drug purchase quantities. We also estimated the excess costs attributable to the difference between prices for generics in Brazil and the lowest global prices for these drugs. Finally, we estimated the savings attributable to Brazil's reduced prices for patented drugs. Negotiated drug prices in Brazil are lowest for patented ARVs for which generic competition is emerging. In recent years, the prices for efavirenz and lopinavir–ritonavir (lopinavir/r) have been lower in Brazil than in other middle-income countries. In contrast, the price of tenofovir is US$200 higher per patient per year than that reported in other middle-income countries. Despite precipitous price declines for four patented ARVs, total Brazilian drug expenditures doubled, to reach US$414 million in 2005. We find that the major driver of cost increases was increased purchase quantities of six specific drugs: patented lopinavir/r, efavirenz, tenofovir, atazanavir, enfuvirtide, and a locally produced generic, fixed-dose combination of zidovudine and lamivudine (AZT/3TC). Because prices declined for many of the patented drugs that constitute the largest share of drug costs, nearly the entire increase in overall drug expenditures between 2001 and 2005 is attributable to increases in drug quantities. Had all drug quantities been held constant from 2001 until 2005 (or for those drugs entering treatment guidelines after 2001, held constant between the year of introduction and 2005), total costs would have increased by only an estimated US$7 million. We estimate that in the absence of price declines for patented drugs, Brazil would have spent a cumulative total of US$2 billion on drugs for HAART between 2001 and 2005, implying a savings of US$1.2 billion from price declines. Finally, in comparing Brazilian prices for locally produced generic ARVs to the lowest international prices meeting global pharmaceutical quality standards, we find that current prices for Brazil's locally produced generics are generally much higher than corresponding global prices, and note that these prices have risen in Brazil while declining globally. We estimate the excess costs of Brazil's locally produced generics totaled US$110 million from 2001 to 2005.
Conclusions
Despite Brazil's more costly generic ARVs, the net result of ARV price changes has been a cost savings of approximately US$1 billion since 2001. HAART costs have nevertheless risen steeply as Brazil has scaled up treatment. These trends may foreshadow future AIDS treatment cost trends in other developing countries as more people start treatment, AIDS patients live longer and move from first-line to second and third-line treatment, AIDS treatment becomes more complex, generic competition emerges, and newer patented drugs become available. The specific application of the Brazilian model to other countries will depend, however, on the strength of their health systems, intellectual property regulations, epidemiological profiles, AIDS treatment guidelines, and differing capacities to produce drugs locally.
Amy Nunn and colleagues analyze the cost of antiretroviral drugs in Brazil between 2001 and 2005 and discuss the implications for HIV treatment in other developing countries.
Editors' Summary
Background.
Acquired immunodeficiency syndrome (AIDS) has killed 29 million people since the first case occurred in 1981 and an estimated 40 million people live with HIV/AIDS today. AIDS is caused by the human immunodeficiency virus (HIV), which destroys the immune system. Infected individuals are consequently very susceptible to other infections. Early in the AIDS epidemic, most HIV-positive individuals died within a few years of becoming infected. Then, in 1996, highly active antiretroviral therapy (HAART)—a cocktail of antiretroviral drugs (ARVs)—was developed. For people who could afford HAART (which holds HIV infections in check), AIDS became a chronic disease. People who start HAART must keep taking it or their illness will progress.
Unfortunately, few people in low- and middle-income countries could afford these expensive drugs. In 2001, ARV prices fell in developing countries as AIDS activists and developing country governments challenged pharmaceutical companies about ARV prices, pharmaceutical companies set tiered prices for the low- and middle-income countries and more generic (inexpensive copies of brand-named drugs) ARVs became available. In 2003, the lack of access to HIV/AIDS treatment was declared a global health emergency. Governments, international organizations, and funding bodies began to set targets and provide funds to increase access to HAART in developing countries. By 2007, over 2 million people in low- and middle-income countries had access to HAART, but another 5 million remain in urgent need of drugs for treatment.
Why Was This Study Done?
In 1995, many countries in the world signed the World Trade Organization (WTO) Trade-Related Aspects of Intellectual Property (TRIPS) agreement, which requires countries to acknowledge intellectual property rights for many products, including pharmaceuticals. In 1996, Brazil became the first developing country to commit to and implement policies to provide free and universal access to HAART. Since then, Brazil's successful AIDS treatment program has become a model for the developing world, and 180,000 Brazilians were receiving HAART at the end of 2006. However, as a WTO member that signed on to the TRIPS agreement, Brazil was required to recognize the intellectual property rights of pharmaceutical companies' patented ARVs. As Brazil scaled up treatment in the late 1990s, the cost of treating AIDS patients rose quickly and the country took controversial public policy steps to reduce the cost of providing HAART to people living with HIV/AIDS. Brazil produces several non-patented ARVs locally, and since 2001 has challenged multinational pharmaceutical companies about the prices of patented ARVs. To induce price reductions for patented ARVs, Brazil has threatened to issue compulsory licenses (which under WTO terms allow countries facing a health emergency to produce patented drugs without consent of the company holding the patent). Brazil also recently issued a compulsory license for one ARV.
Although world leaders have set a target of universal access to HAART by 2010, little is known about the long-term costs of AIDS treatment in developing countries. In this study, the researchers have investigated how and why the costs of ARVs changed in Brazil between 2001 and 2005 and discuss the relevance of the Brazilian model for AIDS treatment for other resource-limited settings.
What Did the Researchers Do and Find?
The researchers analyzed the prices for each ARV recommended in Brazil's therapeutic guidelines for adults and estimated the changes in purchase quantities for each between 2001 and 2005. These changes likely stem from the growing number of options in Brazil's treatment guidelines, the steadily rising number of patients commencing treatment, and patients' shifts to second- and third-line treatments when their HIV infection became resistant to first-line drugs or they developed side effects. The researchers report that the generic drugs produced in Brazil were generally more expensive than similar drugs made elsewhere, but Brazil's negotiated drug prices for many patented ARVs were lower than elsewhere. Overall, total annual drug expenditure on ARVs doubled between 2001 and 2005, reaching US$414 million in 2005. Because many drug prices fell sharply as a result of declining patented drug prices over the study period, this increase was mainly attributable to increases in drug quantities purchased. If these quantities had stayed constant, the total annual cost would have increased by only $7 million, to $211 million. Conversely, without the decrease in the price of patented drugs, Brazil would have spent $952 million annually by 2005. If Brazil had enjoyed the lowest global prices for generic medicines, the total costs per year in 2005 would have been $367 million, or nearly $50 million less than the costs Brazil actually realized.
What Do These Findings Mean?
These findings tease out the many factors—clinical, commercial, and political—that affected the total costs of the Brazilian AIDS treatment program between 2001 and 2005.
Brazil's ability to produce generic drugs facilitated Brazil's price negotiations for patented drugs. Although Brazil saved approximately US$1 billion over the study period as a result of declining prices for patented medicines, the cost of producing generic drugs locally has risen while the prices for generic drugs have fallen elsewhere. Brazil's recent decision to import a generic ARV using a compulsory license suggests that the Brazilian model for AIDS treatment continues to evolve.
Questions remain about the precise causes of year-to-year cost trends in Brazil because, for example, the researchers did not have full data on when patients switched from first-line to second- or third-line drugs. The observed steep rise in costs from 2004 to 2005 in particular warrants further analysis. In addition, the findings may not be generalizable to countries with different policies on HIV/AIDS treatment, different access to generic drugs, or different bargaining power with multinational drug companies. Nevertheless, the trends this study highlights provide important information about how AIDS treatment costs are likely to evolve in other developing countries as efforts are made to provide universal access to life-saving ARVs.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040305.
Information from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
Information from the US Centers for Disease Control and Prevention on global HIV/AIDS topics (in English and Spanish)
HIV InSite, comprehensive and up-to-date information on all aspects of HIV/AIDS from the University of California San Francisco
Information from Avert, an international AIDS charity, on HIV and AIDS in Brazil and on HIV/AIDS treatment and care, including universal access to ARVs
Progress towards universal access to HIV/AIDS treatment, the latest report from the World Health Organization (available in several languages)
The National STD and AIDS Program of Brazil
doi:10.1371/journal.pmed.0040305
PMCID: PMC2071936  PMID: 18001145
16.  The Impact of HAART on the Respiratory Complications of HIV Infection: Longitudinal Trends in the MACS and WIHS Cohorts 
PLoS ONE  2013;8(3):e58812.
Objective
To review the incidence of respiratory conditions and their effect on mortality in HIV-infected and uninfected individuals prior to and during the era of highly active antiretroviral therapy (HAART).
Design
Two large observational cohorts of HIV-infected and HIV-uninfected men (Multicenter AIDS Cohort Study [MACS]) and women (Women’s Interagency HIV Study [WIHS]), followed since 1984 and 1994, respectively.
Methods
Adjusted odds or hazards ratios for incident respiratory infections or non-infectious respiratory diagnoses, respectively, in HIV-infected compared to HIV-uninfected individuals in both the pre-HAART (MACS only) and HAART eras; and adjusted Cox proportional hazard ratios for mortality in HIV-infected persons with lung disease during the HAART era.
Results
Compared to HIV-uninfected participants, HIV-infected individuals had more incident respiratory infections both pre-HAART (MACS, odds ratio [adjusted-OR], 2.4; 95% confidence interval [CI], 2.2–2.7; p<0.001) and after HAART availability (MACS, adjusted-OR, 1.5; 95%CI 1.3–1.7; p<0.001; WIHS adjusted-OR, 2.2; 95%CI 1.8–2.7; p<0.001). Chronic obstructive pulmonary disease was more common in MACS HIV-infected vs. HIV-uninfected participants pre-HAART (hazard ratio [adjusted-HR] 2.9; 95%CI, 1.02–8.4; p = 0.046). After HAART availability, non-infectious lung diseases were not significantly more common in HIV-infected participants in either MACS or WIHS participants. HIV-infected participants in the HAART era with respiratory infections had an increased risk of death compared to those without infections (MACS adjusted-HR, 1.5; 95%CI, 1.3–1.7; p<0.001; WIHS adjusted-HR, 1.9; 95%CI, 1.5–2.4; p<0.001).
Conclusion
HIV infection remained a significant risk for infectious respiratory diseases after the introduction of HAART, and infectious respiratory diseases were associated with an increased risk of mortality.
doi:10.1371/journal.pone.0058812
PMCID: PMC3595204  PMID: 23554932
17.  Effectiveness of option B highly active antiretroviral therapy (HAART) prevention of mother-to-child transmission (PMTCT) in pregnant HIV women 
BMC Research Notes  2014;7:52.
Background
Ensuring that no baby is born with HIV is an essential step towards achieving an AIDS-free generation. To achieve this, strategies that decouple links between childbirth and HIV transmission are necessary. Traditional forms of prevention of mother-to-child transmission of HIV (PMTCT), has been recommended. Recognizing the importance and challenges of combination of methods to achieve rapid PMTCT, the World Health Organization (WHO) recommended option B Highly Active Antiretroviral Therapy (HAART) for all HIV-positive pregnant women. This study aimed to evaluate the effectiveness of the HAART in PMTCT. A cohort of HIV-infected pregnant women in Kenya were obtained from the DREAM Center, Nairobi. The study participants underwent adherence counselling and Option B of HAART [Nevirapine(NVP) + Lamivudine + Zidovudine] at the fourth week of gestation followed by an intravenous NVP administration intrapartum and postpartum NVP syrup to the respective infants for six weeks. Absolute pre-HAART and post-HAART CD4 counts and viral loads counts were determined. Comparison of the CD4 counts and viral loads before and after administration of HAART were done using Wilcoxon’s Matched Pairs Signed-Ranks Test.
Findings
The mean absolute CD4 cell counts in mothers after administration of HAART was significantly higher (Z = 15.664, p < 0.001) than before the administration of HAART). Also the viral load of the mothers significantly (Z = 11.324, p < 0.001) reduced following HAART treatment. Following the HAART administration in mothers, up to 90% of children were confirmed to be HIV negative.
Conclusion
Administration of HAART to mothers and children demonstrated an effective mechanism of PMTCT. However, other aspects of HAART such as adherence, costs, mothers behaviour during HAART, and the child feeding programme during the therapy should further be evaluated and ascertained how they can affect the overall efficacy of option B HAART in PMTCT.
doi:10.1186/1756-0500-7-52
PMCID: PMC3898637  PMID: 24447387
Antiretroviral; CD4 counts; Early Infant Diagnosis; Highly Active Antiretroviral Therapy (HAART); Mother-To-Child Transmission (MTCT); Prevention of Mother-To-Child Transmission (PMTCT)
18.  The effects of exercise training on quality of life in HAART-treated HIV-positive Rwandan subjects with body fat redistribution 
Objective
Our objective was to examine the effects of exercise training (EXS) on quality of life (QoL) in highly active antiretroviral therapy (HAART)-treated HIV-positive (HIV+) subjects with body fat redistribution (BFR) in Rwanda.
Methods
The effects of a randomised controlled trial of EXS on QoL were measured using World Health Organisation Quality of Life (WHOQOL)-BREF in HIV+ subjects with BFR randomised to EXS (n = 50; BFR + EXS) or no exercise training (n = 50; BFR + noEXS).
Results
At 6 months, scores on the psychological [1.3 (0.3) vs. 0.5 (0.1); P < 0.0001], independence [0.6 (0.1) vs. 0.0 (0.0); P < 0.0001], social relationships [0.6 (0.2) vs. 0.0 (0.0); P < 0.0001] and HIV HAART-specific QoL domains [1.4 (0.2) vs. −0.1 (0.2); P < 0.0001] improved more in BFR + EXS than BFR + noEXS group, respectively. Self-esteem [1.3 (0.8) vs. 0.1 (0.6); P < 0.001], body image [1.5 (0.6) vs. 0.0 (0.5); P < 0.001] and emotional stress [1.6 (0.7) vs. 0.2 (0.5); P < 0.001] improved more in the BFR + EXS group than BFR + noEXS group, respectively. Psychological [1.5 (0.2) vs. 1.1 (0.3); P < 0.0001], social relationship [0.8 (0.2) vs. 0.4 (0.2); P < 0.0001], and HIV HAART-specific well-being [1.8 (0.2) vs. 1.0 (0.0); P < 0.0001] improved more in BFR + EXS female than male subjects.
Conclusions
Exercise training improved several components of QoL in HAART-treated HIV+ African subjects with BFR. Exercise training is an inexpensive and efficacious strategy for improving QoL in HIV+ African subjects, which may improve HAART adherence and treatment initiatives in resource-limited areas of sub-Saharan Africa.
doi:10.1007/s11136-008-9319-4
PMCID: PMC3167195  PMID: 18320351
Africa; HAART; Lipodystrophy; Rwanda
19.  Switching HIV Treatment in Adults Based on CD4 Count Versus Viral Load Monitoring: A Randomized, Non-Inferiority Trial in Thailand 
PLoS Medicine  2013;10(8):e1001494.
Using a randomized controlled trial, Marc Lallemant and colleagues ask if a CD4-based monitoring and treatment switching strategy provides a similar clinical outcome compared to the standard viral load-based strategy for adults with HIV in Thailand.
Please see later in the article for the Editors' Summary
Background
Viral load (VL) is recommended for monitoring the response to highly active antiretroviral therapy (HAART) but is not routinely available in most low- and middle-income countries. The purpose of the study was to determine whether a CD4-based monitoring and switching strategy would provide a similar clinical outcome compared to the standard VL-based strategy in Thailand.
Methods and Findings
The Programs for HIV Prevention and Treatment (PHPT-3) non-inferiority randomized clinical trial compared a treatment switching strategy based on CD4-only (CD4) monitoring versus viral-load (VL). Consenting participants were antiretroviral-naïve HIV-infected adults (CD4 count 50–250/mm3) initiating non-nucleotide reverse transcriptase inhibitor (NNRTI)-based therapy. Randomization, stratified by site (21 public hospitals), was performed centrally after enrollment. Clinicians were unaware of the VL values of patients randomized to the CD4 arm. Participants switched to second-line combination with confirmed CD4 decline >30% from peak (within 200 cells from baseline) in the CD4 arm, or confirmed VL >400 copies/ml in the VL arm. Primary endpoint was clinical failure at 3 years, defined as death, new AIDS-defining event, or CD4 <50 cells/mm3. The 3-year Kaplan-Meier cumulative risks of clinical failure were compared for non-inferiority with a margin of 7.4%. In the intent to treat analysis, data were censored at the date of death or at last visit. The secondary endpoints were difference in future-drug-option (FDO) score, a measure of resistance profiles, virologic and immunologic responses, and the safety and tolerance of HAART. 716 participants were randomized, 356 to VL monitoring and 360 to CD4 monitoring. At 3 years, 319 participants (90%) in VL and 326 (91%) in CD4 were alive and on follow-up. The cumulative risk of clinical failure was 8.0% (95% CI 5.6–11.4) in VL versus 7.4% (5.1–10.7) in CD4, and the upper-limit of the one-sided 95% CI of the difference was 3.4%, meeting the pre-determined non-inferiority criterion. Probability of switch for study criteria was 5.2% (3.2–8.4) in VL versus 7.5% (5.0–11.1) in CD4 (p = 0.097). Median time from treatment initiation to switch was 11.7 months (7.7–19.4) in VL and 24.7 months (15.9–35.0) in CD4 (p = 0.001). The median duration of viremia >400 copies/ml at switch was 7.2 months (5.8–8.0) in VL versus 15.8 months (8.5–20.4) in CD4 (p = 0.002). FDO scores were not significantly different at time of switch. No adverse events related to the monitoring strategy were reported.
Conclusions
The 3-year rates of clinical failure and loss of treatment options did not differ between strategies although the longer-term consequences of CD4 monitoring would need to be investigated. These results provide reassurance to treatment programs currently based on CD4 monitoring as VL measurement becomes more affordable and feasible in resource-limited settings.
Trial registration
ClinicalTrials.gov NCT00162682
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 34 million people (most of them living in low-and middle-income countries) are currently infected with HIV, the virus that causes AIDS. HIV infection leads to the destruction of immune system cells (including CD4 cells, a type of white blood cell), leaving infected individuals susceptible to other infections. Early in the AIDS epidemic, most HIV-infected individuals died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (HAART)—combined drugs regimens that suppress viral replication and allow restoration of the immune system—became available. For people living in affluent countries, HIV/AIDS became a chronic condition but, because HAART was expensive, HIV/AIDS remained a fatal illness for people living in resource-limited countries. In 2003, the international community declared HIV/AIDS a global health emergency and, in 2006, it set the target of achieving universal global access to HAART by 2010. By the end of 2011, 8 million of the estimated 14.8 million people in need of HAART in low- and middle-income countries were receiving treatment.
Why Was This Study Done?
At the time this trial was conceived, national and international recommendations were that HIV-positive individuals should start HAART when their CD4 count fell below 200 cells/mm3 and should have their CD4 count regularly monitored to optimize HAART. In 2013, the World Health Organization (WHO) recommendations were updated to promote expanded eligibility for HAART with a CD4 of 500 cells/mm3 or less for adults, adolescents, and older children although priority is given to individuals with CD4 count of 350 cells/mm3 or less. Because HIV often becomes resistant to first-line antiretroviral drugs, WHO also recommends that viral load—the amount of virus in the blood—should be monitored so that suspected treatment failures can be confirmed and patients switched to second-line drugs in a timely manner. This monitoring and switching strategy is widely used in resource-rich settings, but is still very difficult to implement for low- and middle-income countries where resources for monitoring are limited and access to costly second-line drugs is restricted. In this randomized non-inferiority trial, the researchers compare the performance of a CD4-based treatment monitoring and switching strategy with the standard viral load-based strategy among HIV-positive adults in Thailand. In a randomized trial, individuals are assigned different interventions by the play of chance and followed up to compare the effects of these interventions; a non-inferiority trial investigates whether one treatment is not worse than another.
What Did the Researchers Do and Find?
The researchers assigned about 700 HIV-positive adults who were beginning HAART for the first time to have their CD4 count (CD4 arm) or their CD4 count and viral load (VL arm) determined every 3 months. Participants were switched to a second-line therapy if their CD4 count declined by more than 30% from their peak CD4 count (CD4 arm) or if a viral load of more than 400 copies/ml was recorded (VL arm). The 3-year cumulative risk of clinical failure (defined as death, a new AIDS-defining event, or a CD4 count of less than 50 cells/mm3) was 8% in the VL arm and 7.4% in the CD4 arm. This difference in clinical failure risk met the researchers' predefined criterion for non-inferiority. The probability of a treatment switch was similar in the two arms, but the average time from treatment initiation to treatment switch and the average duration of a high viral load after treatment switch were both longer in the CD4 arm than in the VL arm. Finally, the future-drug-option score, a measure of viral drug resistance profiles, was similar in the two arms at the time of treatment switch.
What Do These Findings Mean?
These findings suggest that, in Thailand, a CD4 switching strategy is non-inferior in terms of clinical outcomes among HIV-positive adults 3 years after beginning HAART when compared to the recommended viral load-based switching strategy and that there is no difference between the strategies in terms of viral suppression and immune restoration after 3-years follow-up. Importantly, however, even though patients in the CD4 arm spent longer with a high viral load than patients in the VL arm, the emergence of HIV mutants resistant to antiretroviral drugs was similar in the two arms. Although these findings provide no information about the long-term outcomes of the two monitoring strategies and may not be generalizable to routine care settings, they nevertheless provide reassurance that using CD4 counts alone to monitor HAART in HIV treatment programs in resource-limited settings is an appropriate strategy to use as viral load measurement becomes more affordable and feasible in these settings.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001494.
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); its 2010 recommendations for antiretroviral therapy for HIV infection in adults and adolescents are available as well as the June 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach
The 2012 UNAIDS World AIDS Day Report provides up-to-date information about the AIDS epidemic and efforts to halt it
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on the global HIV/AIDS epidemic, on HIV and AIDS in Thailand, on universal access to AIDS treatment, and on starting, monitoring and switching HIV treatment (in English and Spanish)
The UK National Health Service Choices website provides information (including personal stories) about HIV and AIDS
More information about this trial (the PHPT-3 trial) is available
Patient stories about living with HIV/AIDS are available through Avert; the nonprofit website Healthtalkonline also provides personal stories about living with HIV, including stories about HIV treatment
doi:10.1371/journal.pmed.1001494
PMCID: PMC3735458  PMID: 23940461
20.  Associations of cardiovascular variables and HAART with cognition in middle-aged HIV-infected and uninfected women 
Journal of neurovirology  2011;17(5):469-476.
Despite use of HAART, cognitive impairment remains prevalent in HIV. Indeed, a recent study suggested that in certain instances, stopping HAART was associated with improved cognitive function (Robertson et al. 2010). HAART is occasionally associated with cardiovascular pathology and such pathology may be associated with cognitive impairment. To explore these associations, we assessed the relative contributions of cardiovascular variables such as hypertension and atherosclerosis, of HIV and HAART to cognition. Participants were members of the Women’s Interagency HIV Study (WIHS). In analysis of cross-sectional data using general linear models we assessed the relationship between each cardiovascular variable and Stroop interference time and symbol digit modalities test while adjusting for age, HIV, education, depression, and race/ethnicity. We also analyzed the association of summary measures of HAART use with cognition. In multivariate models significance was limited to carotid lesions and carotid intima-medial thickness quintile (CIMT) with Stroop interference time (for carotid lesions, coefficient = 10.5, CI: 3.5 to 17.5, p = 0.003, N = 1130; for CIMT quintile, coefficient = 8.6, CI = 1.7 to 15.4, p = 0.025, N = 1130). Summary measures of protease inhibitor use and other HAART measures were in most cases not associated with cognitive score in multivariate models. We conclude that in the HAART era among middle-aged women with HIV, carotid disease may be significantly associated with some measures of cognitive impairment. In this cross-sectional study, we could detect neither positive nor negative effects of HAART on cognition.
doi:10.1007/s13365-011-0052-3
PMCID: PMC3509940  PMID: 22006469
Cognition; HIV; Women; Hypertension; Atherosclerosis; Middle-Aged
21.  The Effect of Highly Active Antiretroviral Therapy on the Survival of HIV-Infected Children in a Resource-Deprived Setting: A Cohort Study 
PLoS Medicine  2011;8(6):e1001044.
This observational cohort study by Andrew Edmonds and colleagues reports that treatment with highly active antiretroviral therapy (HAART) markedly improves the survival of HIV-infected children in Kinshasa, DRC, a resource-deprived setting.
Background
The effect of highly active antiretroviral therapy (HAART) on the survival of HIV-infected children has not been well quantified. Because most pediatric HIV occurs in low- and middle-income countries, our objective was to provide a first estimate of this effect among children living in a resource-deprived setting.
Methods and Findings
Observational data from HAART-naïve children enrolled into an HIV care and treatment program in Kinshasa, Democratic Republic of the Congo, between December 2004 and May 2010 were analyzed. We used marginal structural models to estimate the effect of HAART on survival while accounting for time-dependent confounders affected by exposure. At the start of follow-up, the median age of the 790 children was 5.9 y, 528 (66.8%) had advanced or severe immunodeficiency, and 405 (51.3%) were in HIV clinical stage 3 or 4. The children were observed for a median of 31.2 mo and contributed a total of 2,089.8 person-years. Eighty children (10.1%) died, 619 (78.4%) initiated HAART, six (0.8%) transferred to a different care provider, and 76 (9.6%) were lost to follow-up. The mortality rate was 3.2 deaths per 100 person-years (95% confidence interval [CI] 2.4–4.2) during receipt of HAART and 6.0 deaths per 100 person-years (95% CI 4.1–8.6) during receipt of primary HIV care only. The mortality hazard ratio comparing HAART with no HAART from a marginal structural model was 0.25 (95% CI 0.06–0.95).
Conclusions
HAART reduced the hazard of mortality in HIV-infected children in Kinshasa by 75%, an estimate that is similar in magnitude but with lower precision than the reported effect of HAART on survival among children in the United States.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2009, an estimated 2.5 million children were living with HIV, the majority of whom (2.3 million) were in sub-Saharan Africa. Most (90%) of these children acquired HIV from their HIV-infected mothers during pregnancy, birth, or breastfeeding, highlighting the importance of giving effective drugs for the prevention of mother to child transmission. As such interventions are still not widely accessible or available in most resource-limited countries, where the burden of HIV is highest, every day an estimated 1,000 children were newly infected with HIV in 2009, but only 360,000 children were receiving highly active antiretroviral therapy (HAART).
Although HAART improves the survival of adults living with HIV, less is known about the degree to which HAART affects the survival of HIV-infected children—although response to antiretroviral treatment is known to differ across age groups. Furthermore, as the course of HIV disease in children is different from that in adults (partly because of the impact of the virus on the immature thymus, which can lead to high HIV RNA viremia and rapid death), it is inappropriate to extrapolate results from studies of adults to pediatric populations. Therefore, it is imperative that the effect of HAART on survival be quantified specifically in children.
Why Was This Study Done?
Most observational studies of the effects of treatment on child survival have been undertaken in high-income countries, such as Italy and the United States. As most children with HIV live in low-resource areas, where multiple factors, such as delayed presentation to care and a higher incidence of co-occurring conditions, might adversely affect treatment outcomes, there is a specific need for information on the effects of HAART in children with HIV living in low-income countries. Although some investigations have taken place in pediatric cohorts from such countries (for example, Côte d'Ivoire, Haiti, Lesotho, Thailand, and Zambia), the effect of HAART on mortality has not been accurately quantified among children in a resource-deprived setting. Therefore, in this observational clinical cohort study, the researchers investigated the effect of HAART on mortality in HIV-infected children in Kinshasa, in the Democratic Republic of the Congo (DRC).
What Did the Researchers Do and Find?
The researchers analyzed data from 790 children enrolled into an HIV program in Kinshasa, DRC, between December 2004 and May 2010 and used a statistical model (marginal structural models) to adjust for time-dependent confounding factors, such as the fact that HAART is typically initiated in sicker patients, for example, those with lower CD4 cell percentages. Assuming that all children starting HAART received it uninterruptedly throughout follow-up, using this statistical model, the researchers were able to compare the hazard ratio of death had all children initiated HAART to that had no children initiated HAART during follow-up.
In the study, 619 out of the 790 children (78.4%) initiated HAART during follow-up and were followed for a median of 31.2 months, with a median of 30 HIV care visits. Of those who started treatment, 110 (17.8%) switched to an alternative regimen because of an adverse event or treatment failure. During the 2,089.8 accrued person-years of follow-up, 80 children (10.1%) died, giving an overall mortality rate of 3.8 deaths per 100 person-years. The unadjusted mortality rate ratio comparing HAART to no HAART was 0.54. Using a marginal structural model, the researchers estimated that compared to no HAART, HAART reduced the hazard (rate) of mortality during follow-up by 75%.
What Do These Findings Mean?
These findings show that treatment with HAART markedly improved the survival of children infected with HIV in Kinshasa, DRC, and suggest that HAART is as effective in improving the survival of HIV-infected children in a severely resource-deprived country (still recovering from civil war) as in more resource-privileged settings—an important finding given that the vast majority of children receiving HAART live in resource-poor areas. This study provides additional evidence that accelerating rollout of antiretroviral therapy to children with HIV in resource-poor countries is lifesaving and effective. Future research needs to address how effective HAART is in understudied populations in resource-poor countries, such as undernourished children or those with co-infections such as tuberculosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001044.
The World Health Organization's Web site has more information about the treatment of children living with HIV
Médecins Sans Frontières's Campaign for Access to Essential Medicines Web site has more information on pediatric HAART
doi:10.1371/journal.pmed.1001044
PMCID: PMC3114869  PMID: 21695087
22.  Highly active antiretroviral therapy and hospital readmission: comparison of a matched cohort 
Background
Despite the known efficacy of highly active antiretroviral therapy (HAART), a large proportion of potentially-eligible HIV-infected patients do not access, and may stand to benefit from this treatment. In order to quantify these benefits in terms of reductions in hospitalizations and hospitalization costs, we sought to determine the impact of HAART on hospital readmission among HIV-infected patients hospitalized at St. Paul's Hospital (SPH) in Vancouver, BC, Canada.
Methods
All patients admitted to a specialized HIV/AIDS ward at SPH (Apr. 1997 – Oct. 2002) were selected and classified as being on HAART or not on HAART based upon their initial admission. Patients were then matched by their propensity scores, which were calculated based on patients' sociodemographics such as age, gender, injection drug use (IDU) status, and AIDS indication, and followed up for one year. Multivariate logistic regression was used to estimate the difference in the odds of hospital readmission between patients on and not on HAART.
Results
Out of a total 1084 patients admitted to the HIV/AIDS ward between 1997 and 2002, 662 were matched according to their propensity score; 331 patients each on and not on HAART. Multivariate logistic regression revealed that patients on HAART had lower odds of AIDS hospital readmission (OR, 0.61; 95% CI, 0.42 – 0.89) compared to patients not on HAART. Odds of readmission among patients on HAART were also significantly lower for non-IDU related readmission (OR, 0.73; 95% CI, 0.53 – 0.99) and overall readmission (OR, 0.72; 95% CI, 0.53 – 0.98).
Conclusion
Propensity score matching allowed us to reliably estimate the association between exposure (on or not on HAART) and outcome (readmitted to hospital). We found that HIV-infected patients who were potentially eligible for, but not on HAART had higher odds of being readmitted to hospital compared to those on HAART. Given the low level of uptake (31%) of HAART observed in our pre-matched hospitalized cohort, a large potential to achieve clinical benefits, reduce hospitalization costs and possibly slow disease progression from improved HAART uptake still exists.
doi:10.1186/1471-2334-6-146
PMCID: PMC1617096  PMID: 17022826
23.  Cardiac Status of HIV-Infected Children Treated With Long-Term Combination Antiretroviral Therapy: Results from the Adolescent Master Protocol of the NIH Multicenter Pediatric HIV/AIDS Cohort Study 
JAMA pediatrics  2013;167(6):520-527.
Objective
To determine the cardiac effects of prolonged exposure to highly active antiretroviral therapy (HAART) on HIV-infected (HIV+) children.
Design
In the National Institutes of Health (NIH)-funded Pediatric HIV/AIDS Cohort Study’s Adolescent Master Protocol (AMP), we used linear regression models to compare echocardiogram measures.
Setting
14 U.S. pediatric HIV clinics.
Patients/Participants
Perinatally-infected HIV+ children receiving HAART with HIV-exposed but uninfected (HEU) children and HIV+ (mostly HAART-unexposed) historical pediatric controls from the NIH-funded Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2-HIV) Study.
Main Exposure
Long-term HAART.
Outcome Measures
Echocardiographic measures of left ventricular (LV) function and structure.
Results
The 325 AMP HIV+ children had lower viral loads, higher CD4 counts, and longer duration of antiretroviral therapy than 70 P2C2 HIV+ children (all P’s < 0·001). Z scores for LV fractional shortening (a measure of cardiac function) were significantly lower among P2C2 HIV+ children than among the AMP HIV+ group or the 189 AMP HEU controls (P < 0.05). For HIV+ children, lower nadir CD4 percentage and higher current viral load were associated with significantly lower cardiac function (LV contractility and LV fractional shortening Z scores; P’s = 0.001) and increased LV end-systolic dimension Z score (P’s < 0.03). In an interaction analysis by HIV+ cohort, P2C2 HIV+ children with longer ART exposure or lower nadir CD4 percentage had lower mean LV fractional shortening Z scores, while mean Z scores were relatively constant among AMP HIV+ children (P<0·05 for all interactions).
Conclusions
HAART appears to be cardioprotective in HIV+ children and adolescents.
doi:10.1001/jamapediatrics.2013.1206
PMCID: PMC4180681  PMID: 23608879
24.  The Impact of Kidney Function at HAART Initiation on Mortality in HIV-infected Women 
Background
In the early highly active antiretroviral therapy (HAART) era, kidney dysfunction was strongly associated with death among HIV-infected individuals. We re-examined this association in the later HAART period to determine whether chronic kidney disease (CKD) remains a predictor of death after HAART-initiation.
Methods
To evaluate the effect of kidney function at the time of HAART initiation on time to all-cause mortality, we evaluated 1415 HIV-infected women initiating HAART in the Women’s Interagency HIV Study (WIHS). Multivariable proportional hazards models with survival times calculated from HAART initiation to death were constructed; participants were censored at the time of the last available visit or December 31, 2006.
Results
CKD (eGFR <60 ml/min/1.73 m2) at HAART initiation was associated with higher mortality risk adjusting for age, race, hepatitis C serostatus, AIDS history and CD4+ cell count (hazard ratio [HR]=2.23, 95% confidence interval [CI]: 1.45–3.43). Adjustment for hypertension and diabetes history attenuated this association (HR=1.89, CI: 0.94–3.80). Lower kidney function at HAART initiation was weakly associated with increased mortality risk in women with prior AIDS (HR=1.09, CI: 1.00–1.19, per 20% decrease in eGFR).
Conclusions
Kidney function at HAART initiation remains an independent predictor of death in HIV-infected individuals, especially in those with a history of AIDS. Our study emphasizes the necessity of monitoring kidney function in this population. Additional studies are needed to determine mechanisms underlying the increased mortality risk associated with CKD in HIV-infected persons.
doi:10.1097/QAI.0b013e3181e674f4
PMCID: PMC3243740  PMID: 20581688
kidney disease; mortality; HIV; WIHS; antiretroviral therapy
25.  Tenofovir use and urinary biomarkers among HIV-infected women in the Women's Interagency HIV Study (WIHS) 
Background
Tenofovir has been associated with renal tubular injury. Biomarkers that signal early tubular dysfunction are needed because creatinine rise lags behind tenofovir-associated kidney dysfunction. We examined several urinary biomarkers to determine if rises accompanying tenofovir initiation preceded creatinine changes.
Methods
Three urinary biomarkers of tubular impairment- neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl- β -D-glucosaminidase (NAG), and β-2-microglobulin (β2MG)-were measured across three time points (one pre-tenofovir visit and two post tenofovir visits) in one hundred and thirty two HIV-positive women from the Women's Interagency HIV Study (WIHS). Women initiating HAART containing tenofovir were propensity score matched to women initiating HAART without tenofovir and women not on HAART.
Results
There were no differences between groups for NGAL or NAG but β2MG was 19 times more likely to be elevated among tenofovir users at the 2nd post tenofovir visit compared to non-TDF users at the pre-tenofovir visit (p<0.01). History of proteinuria was associated with elevated NGAL (p <0.01). Factors associated with elevated NAG were GFR<60 ml/min, history of proteinuria, hepatitis C (p<0.01 for all) and diabetes mellitus (p=0.05). Factors associated with increased odds of elevated β2MG were HIV RNA>100,000 copies/ml, hepatitis C, boosted protease inhibitor (PI) use, and GFR<60 ml/min (p≤0.01 for all).
Conclusions
β2MG levels are elevated in women on tenofovir indicating probable early renal dysfunction. Biomarker elevation is additionally associated with baseline chronic kidney disease, uncontrolled viremia, and boosted PI use. Future studies are needed to explore urinary biomarker thresholds in identifying treated HIV-infected individuals at risk for renal dysfunction.
doi:10.1097/QAI.0b013e31828175c9
PMCID: PMC3692572  PMID: 23254151
Tenofovir; urinary biomarkers; HIV infected women

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