Benefit Of Highly Active Antiretroviral Therapy Research Articles

Prevalence of and risk factors for methicillin-resistant Staphylococcus aureus colonization among human immunodeficient virus–infected outpatients in Taiwan: oral Candida colonization as a comparator

ABSTRACTHuman immuodeficency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) and community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) have increased in recent years in Taiwan. This study was undertaken to determine the prevalence of and risk factors for nasal and oral S. aureus and MRSA colonization among contemporary HIV-infected populations. Clinical variables for S. aureus and MRSA colonization among HIV-infected outpatients from three hospitals were analyzed and compared with those for oral Candida colonization. Genetic characteristics of MRSA isolates were analyzed. A total of 714 patients were screened for nasal S. aureus colonization, and a subset of 457 patients were also screened for oral S. aureus colonization. Of all patients, 79.4% were receiving HAART, and their mean CD4 count was 472 cells/mm3. The colonization rates in the oral cavity, nasal cavity, and at either site were 18.8%, 31.7%, and 36.8%, respectively, for S. aureus, and 3.1%, 4.4%, and 5.5%, respectively, for MRSA. These rates were all much lower than the previously reported rate of oral Candida colonization (52.4%). By multivariate analysis, a suppressed viral load (<200 copies/mL) protected against oral S. aureus, MRSA, and Candida colonization, and recent use of antibacterial agents protected against oral and nasal S. aureus colonization. Recent incarceration increased the risk of nasal MRSA colonization, while recent hospitalization, tuberculosis, older age, and intravenous drug use increased the risk of oral Candida colonization. Candida spp. did not augment S. aureus or MRSA colonization in the oral cavity. Most of the 41 MRSA isolates recovered belonged to the SCCmec IV/pvl-negative (51.2%) and VT/pvl-positive (26.8%) ST59 local prevalent CA-MRSA clones. Distinct carriage rates demonstrated here suggested that mucosal immunity against colonization might differ in terms of microbes and sites. A decreased risk in oral carriage of MRSA and Candida might be a benefit of HAART.

Should highly active antiretroviral therapy be prescribed in critically ill HIV-infected patients during the ICU stay? A retrospective cohort study

BackgroundThe impact of highly active antiretroviral therapy (HAART) in HIV-infected patients admitted to the intensive care unit (ICU) remains controversial. We evaluate impact of HAART prescription in HIV-infected patients admitted to the ICU of Tourcoing Hospital from January 2000 to December 2009.ResultsThere were 91 admissions concerning 85 HIV-infected patients. Reasons for ICU admission were an AIDS-related diagnosis in 46 cases (51%). Fifty two patients (57%) were on HAART at the time of ICU admission, leading to 21 immunovirologic successes (23%). During the ICU stay, HAART was continued in 29 patients (32%), and started in 3 patients (3%). Only one patient experienced an adverse event related to HAART. Mortality rate in ICU and 6 months after ICU admission were respectively 19% and 27%. Kaplan-Meier estimates of the cumulative unajusted survival probability over 6 months were higher in patients treated with HAART during the ICU stay (Log rank: p = 0.04). No benefit of HAART in ICU was seen in the adjusted survival proportion at 6 months or during ICU stay. Prescription of HAART during ICU was associated with a trend to lower incidence of new AIDS-related events at 6 months (respectively 17% and 34% with and without HAART, p = 0.07), and with higher incidence of antiretroviral resistance after ICU stay (respectively 25% and 7% with and without HAART, p = 0.02).ConclusionsOur results suggest a lower death rate over 6 months in critically ill HIV-infected patients taking HAART during ICU stay. The optimal time to prescribe HAART in critically ill patients needs to be better defined.

The Impact of HAART on HPV-Related Cervical Disease

highly active antiretroviral therapy (HAART) has had an unequivocally positive impact on morbidity and mortality in HIV-infected individuals. These benefits have clearly extended to some HIV-related malignancies, including Kaposi's sarcoma and non-Hodgkin's lymphoma. The impact of HAART on cervical cancer, however, remains uncertain. The objective of this review is to summarize the last ten years of registry-based and clinical research into the impact of HAART on human papillomavirus (HPV) related cervical disease. compared to their HIV-uninfected counterparts, HIV-infected women have an increased prevalence of HPV infection, increased risk of progression of HPV-related cervical disease, and an increased risk of invasive cervical cancer. While the partial immune reconstitution afforded by HAART might be expected to decrease susceptibility to HPV infection and cervical disease, the local effects of improved immunosurveillance on the cervix are uncertain and the increased longevity of patients on HAART may increase risk of exposure to HPV and provide the time required for progression of cervical disease. Registry-based evidence has been consistent in identifying the lack of decrease in cervical cancer incidence in the HAART era. Clinical research on the subject, however, has produced conflicting evidence with regards to both the effect of HAART on HPV infection and its impact on cervical disease progression/regression. the incidence of cervical cancer has not decreased in the HAART-era. Furthermore, clinical research has not shown a clear benefit of HAART in decreasing HPV-related cervical disease in HIV-infected women. A better understanding of this subject will have an impact on cervical disease surveillance practices.

Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study

Results of cohort studies and mathematical models have suggested that increased coverage with highly active antiretroviral therapy (HAART) could reduce HIV transmission. We aimed to estimate the association between plasma HIV-1 viral load, HAART coverage, and number of new cases of HIV in the population of a Canadian province. We undertook a population-based study of HAART coverage and HIV transmission in British Columbia, Canada. Data for number of HIV tests done and new HIV diagnoses were obtained from the British Columbia Centre for Disease Control. Data for viral load, CD4 cell count, and HAART use were extracted from the British Columbia Centre for Excellence in HIV/AIDS population-based registries. We modelled trends of new HIV-positive tests and number of individuals on HAART using generalised additive models. Poisson log-linear regression models were used to estimate the association between new HIV diagnoses and viral load, year, and number of individuals on HAART. Between 1996 and 2009, the number of individuals actively receiving HAART increased from 837 to 5413 (547% increase; p=0.002), and the number of new HIV diagnoses fell from 702 to 338 per year (52% decrease; p=0.001). The overall correlation between number of individuals on HAART and number of individuals newly testing positive for HIV per year was -0.89 (p<0.0001). For every 100 additional individuals on HAART, the number of new HIV cases decreased by a factor of 0.97 (95% CI 0.96-0.98), and per 1 log(10) decrease in viral load, the number of new HIV cases decreased by a factor of 0.86 (0.75-0.98). We have shown a strong population-level association between increasing HAART coverage, decreased viral load, and decreased number of new HIV diagnoses per year. Our results support the proposed secondary benefit of HAART used within existing medical guidelines to reduce HIV transmission. Ministry of Health Services and Ministry of Healthy Living and Sport, Province of British Columbia; US National Institute on Drug Abuse; US National Institutes of Health; Canadian Institutes of Health Research.

Hepatitis B vaccine responses in a large U.S. military cohort of HIV-infected individuals: Another benefit of HAART in those with preserved CD4 count

The influence of highly active antiretroviral therapy (HAART) upon hepatitis B virus (HBV) vaccine responses in HIV-infected individuals is unclear. After classification of vaccinees as non-responders (HBsAb <10 IU/L) or responders (HBsAb ≥10 IU/L) in our HIV cohort, multivariate logistic regression was used to assess factors associated with subsequent vaccine response. Of 626 participants vaccinated from 1988 to 2005, 217 (35%) were vaccine responders. Receipt of ≥3 doses of vaccine (OR 1.83, 95% CI 1.24–2.70), higher CD4 count at vaccination (OR 1.09, 95% CI 1.05–1.13 per 50 cells/μl increase), and use of HAART (OR 2.37, 95% CI 1.56–3.62) were all associated with increased likelihood of developing a response. However, only 49% of those on HAART at last vaccination responded, and 62% of those on HAART, with CD4 count ≥350, and HIV RNA <400 copies/mL responded. Compared to those on HAART with CD4 count ≥350, those not on HAART with CD4 count ≥350 had significantly reduced odds of developing a vaccine response (OR 0.47, 95% CI 0.30–0.70). While HAART use concurrent with HBV immunization was associated with increased probability of responding to the vaccine, the response rate was low for those on HAART. These data provide additional evidence of HAART benefits, even in those with higher CD4 counts, but also highlight the need for improving HBV vaccine immunogenicity.

Antiretroviral medications during pregnancy for therapy or prophylaxis

The use of combination antiretroviral therapy during pregnancy has enabled us to decrease perinatal HIV transmission to less than 1%, in areas with adequate resources. Questions remain regarding the safety of these medications for the mother, fetus, and child. Recent publications present conflicting data about associations between antiretrovirals and prematurity and other adverse pregnancy outcomes, and if highly active antiretroviral therapy (HAART) is necessary for all pregnant women. The pharmacokinetics of some antiretroviral medications are altered significantly during pregnancy; placental transfer to the fetus is variable. The well-documented benefit of HAART for preventing mother-to-child transmission generally outweighs the potential risks to the fetus, infant, and mother. However, potential adverse effects are of concern, and questions remain as to the optimal treatment strategy. More data on the effects of antiretrovirals during pregnancy are needed.

Active Tuberculosis Does Not Always Imply the Initiation of Highly Active Antiretroviral Therapy in HIV-Infected Patients

Infection with HIV is an important risk factor for tuberculosis (TB). One-half million cases of TB attributable to HIV infection occur worldwide each year. Since the advent of highly active antiretroviral therapy (HAART) the morbidity and mortality of HIV-infected patients have declined. However concomitant TB treatment and HAART are hampered by a high pill burden complex drug interactions treatment-related adverse events and paradoxic reactions. Studies that have assessed the effect of HAART in the course of TB and HIV coinfection are few. All these retrospective studies suggest that coinfected patients with a CD4 count less than 100 cells/mm/3 would probably benefit from early initiation of HAART. Unlike other HIV-associated opportunistic infections TB may occur at high CD4 cell counts. The indication for HAART in these particular cases has not been assessed and current antiretroviral (ARV) treatment guidelines are based on expert opinion. We evaluated retrospectively 93 episodes of TB diagnosed in 87 HIV-infected patients from January 2000 to February 2004 at Bichat Hospital in an attempt to assess the clinical aspects and outcome of TB according to the level of immunosuppression at TB diagnosis and to the prescription of HAART in the course of TB treatment. (excerpt)

Liver fibrosis on account of chronic hepatitis C is more severe in HIV‐positive than HIV‐negative patients despite antiretroviral therapy

The recent availability of non-invasive tools to measure liver fibrosis has allowed examination of its extent and determination of predictors in all patients with chronic hepatitis C virus (HCV) infection. On the other hand, most information on hepatic fibrosis in HCV/human immunodeficiency virus (HIV)-coinfected patients has been derived from liver biopsies taken before highly active antiretroviral therapy (HAART) was widely available. All consecutive HCV patients with elevated aminotransferases seen during the last 3 years were evaluated and liver fibrosis measured using transient elastography (FibroScan) and biochemical indexes. Patients were split according to their HIV serostatus. A total of 656 (69.6%) HCV-monoinfected and 287 (30.4%) HIV/HCV-coinfected patients were assessed. Mean CD4 count of coinfected patients was 493 cells/muL and 88% were under HAART (mean time, 4.2 +/- 2.4 years). Advanced liver fibrosis or cirrhosis was recognized in 39% of the coinfected and 18% of the monoinfected patients (P < 0.005). A good correlation was found between FibroScan) and biochemical indexes [AST to platelet ratio index (r = 0.405, P < 0.0001), FIB-4 (r = 0.393, P < 0.0001) and Forns (r = 0.407, P < 0.0001)], regardless of the HIV status. In the multivariate analysis, age >45 years, body mass index (BMI) >25 kg/m(2), and HIV infection were independently associated with advanced liver fibrosis or cirrhosis. HIV/HCV-coinfected patients have more advanced liver fibrosis than HCV-monoinfected patients despite the immunologic benefit of HAART.

Cidofovir in combination with HAART and survival in AIDS-associated progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy is a demyelinating disease with a high mortality caused by the JC virus and occurs in about 5% of HIV-infected patients. Highly active anti-retroviral therapy (HAART) has a proven efficacy in prolonging the survival of patients with AIDS-associated PML, but there are differing opinions about adding cidofovir to the treatment of PML. To investigate the benefit of HAART combined with cidofovir, we retrospectively analysed the survival of 33 patients with AIDS-associated PML proven by PCR in CSF, biopsy or at autopsy. Additionally, we also analysed 37 patients with probable PML. Seventeen (51.5%) of the patients with confirmed PML were treated with HAART and 14 (42.4%) with cidofovir in any combination. Of these patients, 13 (39.4%) were treated with HAART and cidofovir in combination, four (12.1%) patients received only HAART without cidofovir and one (3%) patient received only cidofovir without HAART. Fifteen patients did not receive HAART or cidofovir. The cumulative survival was significantly longer in patients with HAART than in patients without HAART (p = 0.006), independent whether cidofovir was given or not. In comparison with single therapy with HAART, the combination of HAART and cidofovir showed no significant increase in survival (p = 0.435). Therefore, a benefit for cidofovir in addition to HAART in the treatment of PML in HIV-infected patients could not be proven.

Emerging epidemiologic observations in HCV/HIV coinfection

Recent studies indicate that when HCV-infected patients also are infected with HIV, their risk of chronic liver disease is increased up to twofold compared with the risk for HCV-infected patients without HIV. As a result, consideration for HCV antiviral therapy should not be hindered by HIV status. The data are inconclusive on the role of highly active antiretroviral therapy (HAART) in chronic liver disease progression. The limited data available do not support an HIV-related increase in the risk of hepatocellular carcinoma in HCV-infected patients. Acute hepatotoxicity clearly increases significantly when HAART is administered to patients infected with both HIV and HCV, compared with patients infected with HIV alone. Nonetheless, the overall benefit of HAART in persons with HIV is far greater than the risk of hepatotoxicity, even with coinfection.

Antiretroviral Therapy for Children

ACCORDING TO THE UNITED NATIONS PROGRAMME on HIV/AIDS (UNAIDS) global report on human immunodeficiency virus (HIV), in 2005 more than 2.3 million children were living with HIV infection, and 380 000 children with HIV had died. Most of the children who die from HIV have severe manifestations of common childhood illnesses, such as diarrhea, malnutrition, acute respiratory tract infection, and tuberculosis. These children often die before the diagnosis of HIV infection can be made, and mortality is often attributed to a background high rate of early childhood mortality. The United States is home for a diminishing proportion of HIV-infected children, with an estimated 11 000 cases in 2005. There are 2 reasons for this decreasing population of HIV-infected children in the developed world. First, pregnant women are increasingly being offered HIV testing, and HIV-infected women are receiving antiretroviral medications sufficient to reduce transmission to a rate of approximately 1% to 2%. Second, the population of HIV-infected children is diminishing because those children who had been infected are now growing up and becoming adults, following the introduction of potent new drugs in 1996. According to a longitudinal study by the Pediatric AIDS Clinical Trials Group (PACTG 219), the mortality rate for HIVinfected children and adolescents decreased from more than 5% in 1996 to less than 1% in 1998. Similar survival benefits have been observed among adults. The impact of highly active antiretroviral therapy (HAART) on survival and quality of life among patients affected by HIV is hardly disputable, but concise objective evidence of the benefit of treatment on infectious complications in children has been lacking in the medical literature. Before the availability of HAART, opportunistic infections such as Pneumocystis jiroveci pneumonia, bacteremia, bacterial pneumonia, and fungal sepsis were significant fatal diseases in patients infected with HIV and remain so among patients not receiving therapy. In this issue of JAMA, Gona and colleagues provide objective evidence to substantiate the benefit of HAART or, more correctly, the association of HAART and opportunistic infection prophylaxis with incidence of opportunistic infections before and after the advent of HAART. In a retrospective cohort study, Gona et al compared the incidence of 29 opportunistic infections in HIV-infected children who were treated in the HAART era with the incidence among those who were treated before the availability of HAART. They found that the incidence of P jiroveci pneumonia had decreased by 14-fold, disseminated Mycobacterium avium complex by 12-fold, bacteremia by 10-fold, and bacterial pneumonia by 5-fold. These reductions in opportunistic infections occurred despite a concomitant reduction in the use of specific prophylaxis medications, suggesting that immune reconstitution rather than improved prophylaxis was primarily responsible for better outcomes. The size and diversity of the population studied allows for generalizability of the results to the US population of children with HIV infection. There were approximately 3000 children in the cohort, which constitutes about 22% of children and adolescents living with HIV in the United States. Given the diminishing population of HIV-infected children, it is unlikely that additional data will become available in this country. There were limitations with the retrospective cohort study design, which evaluated available data from a database. Some events and clinical practices changed over time and could have affected case ascertainment and overall disease incidence. Although the incidence of bacterial pneumonia was reported, the diagnosis of this problem in children is difficult, because no consistent clinical or radiographic features reliably distinguish different etiologies of pneumonia. Radiographic pneumonia may or may not be associated with bacteremia. When such an association occurs, the relationship is not always a causal one. Specific etiologic diagnosis of bacterial pneumonia can be determined by diagnostic techniques, such as lung aspirates or bronchoalveolar lavage. These procedures are highly sensitive but are seldom used because they are considered too invasive.

HIV and Aging

Between 2001 and 2004, the percentage of all HIV cases in patients aged >or=50 years increased from 17% to 23%. This concerning increase is expected to continue over the next decade. The increasing prevalence of HIV in these patients is a result of increased longevity in patients treated with highly active antiretroviral therapy (HAART) as well as new primary infections in older patients. While older patients may achieve virological suppression at the same rate as younger patients, the immunological benefit of HAART in older patients may be reduced compared with younger patients. In addition, the toxicities associated with HAART may be worse in older HIV patients, particularly those with underlying renal or hepatic insufficiency. All previous studies evaluating the virological and immunological benefits of HAART in older patients have had relatively small sample sizes and none has compared efficacy or rates of toxicity by HAART treatment class. Co-morbidities are more common in older than in younger patients and can impact on the management of HIV in these patients. Providers must be cognisant of drug-drug interactions and potential adverse effects of HAART regimens when selecting an ideal antiretroviral regimen for older HIV patients. Given the increased longevity and rates of malignancies in HIV-infected patients, providers should also be particularly vigilant in maintaining routine health screening in older HIV patients. Controlled trials on HIV epidemiology, pathogenesis, and therapeutic and clinical outcomes are also needed in older patients. As the HIV-infected population ages, there is a growing need to better determine the effectiveness of HAART in older patients, and to investigate factors associated with a more rapid course of HIV infection in patients aged >50 years.

Changing pattern of primary cerebral lymphoma in the highly active antiretroviral therapy era

Before the introduction of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV)-related primary central nervous system lymphoma (PCNSL) represented one of the most prevalent causes of focal brain lesions in HIV-infected people. The prognosis of PCNSL was very poor, with median survival time not exceeding 2 months. Brain biopsy was the method of choice for the definitive diagnosis, but it was and remains an invasive procedure with morbidity and mortality as well as considerable costs in terms of patients' management and quality of life. The strict association between AIDS-PCNSL and Epstein-Barr virus led to the suggestion that EBV DNA in cerebrospinal spinal fluid (CSF) might serve as a diagnostic marker, reducing the time required for diagnosis and allowing a minimally invasive approach. The clinical usefulness of this methodology has been largely demonstrated through clinical practice. After the introduction of HAART in clinical practice, a survival benefit has been observed for most persons with acquired immunodeficiency syndrome (AIDS)-associated opportunistic infections and cancers. In particular, for patients with non-Hodgkin lymphoma, a higher likelihood of response to chemotherapy as well as a longer survival has been found as a consequence of the use of combined antiretroviral therapy. Although larger studies did not show significant changes in survival of HIV-infected patients with PCNSL in the era of HAART, small case series and anecdotal reports showed the benefit of HAART in the treatment of PCNSL. Nevertheless, these patients' survival still remains very poor and it could be hypothesized that, other than specific cancer prognostic determinants and severe immunodeficiency, viral pathogenesis as well as EBV-specific immunologic dysfunction may be responsible.

Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease.

The rise in the number of patients with HIV-associated nephropathy and HIV-infection with end-stage renal disease (HIV+ ESRD) continues to be a substantial concern for the ESRD program. In order to assess the impact of highly active antiretroviral therapy (HAART) on the progression of patients with AIDS to the development of ESRD and to project the prevalence of HIV+ ESRD through 2020, a mathematical model of the dynamics of HIV+ infection in the ESRD population was developed. Epidemiologic data on AIDS and HIV+ ESRD among black individuals in the United States were obtained since 1991 from the Centers for Disease Control and Prevention and US Renal Data System, respectively. The model was constructed to predict the prevalence of HIV+ ESRD incorporating the current rate of growth in AIDS prevalence. Two possible trends were considered: linear AIDS growth and exponential AIDS growth. The likely effectiveness of HAART in slowing progression to HIV+ ESRD was estimated from the best fit of the model to the data after 1995, when HAART was introduced. The model was then used to evaluate recent data and to project the prevalence of HIV+ ESRD through 2020. The model suggested that HAART has reduced the rate of progression from AIDS to HIV+ ESRD by 38%. The model projected an increase in HIV+ ESRD prevalence in the future as a result of the increase in the AIDS population among black individuals. This increase was predicted even assuming a 95% reduction in the progression from AIDS to HIV+ ESRD. Despite the potential benefit of HAART, the prevalence of HIV+ ESRD in the United States is expected to rise in the future as a result of the expansion of the AIDS population among black individuals. It is concluded that prevention of progression to ESRD should focus on early antiretroviral treatment of HIV-infected patients who have evidence of HIV-associated nephropathy.

Human Cytomegalovirus Resistance to Antiviral Drugs

Human cytomegalovirus (HCMV) infections are common and lead to lifelong infections. In immunocompetent individuals, primary infections are mostly subclinical or they may be associated with a self-limited mononucleosis-like syndrome. In contrast, infections in immunocompromised hosts (either primary infections, reactivations from latency, or reinfections) are associated with important morbidity and mortality. In patients with AIDS, the introduction of highly active antiretroviral therapy (HAART) has decreased the overall incidence of HCMV disease, mainly retinitis and gastrointestinal infections, by about 80% (50, 105). However, the functional benefit of HAART (i.e., restoration of specific HCMV-specific immune responses) may take up to 3 to 6 months to occur, and some patients do not have access to or do not respond to HAART (3, 40, 67, 104). Thus, HCMV still remains a concern in AIDS patients with CD4 counts <50 to 100 cells/μl. A specific HCMV syndrome consisting of fever, malaise, arthralgia, and neutropenia may occur in solid-organ transplant (SOT) patients, in particular, those developing a primary HCMV infection (i.e., HCMV-seronegative recipient from a HCMV-seropositive donor [D+/R−]) during the first 3 months posttransplantation. In addition, invasive HCMV disease may involve different organs, such as the lungs, liver, and gastrointestinal tract. In the absence of antiviral intervention, symptomatic HCMV infections occur in approximately 39 to 41% of heart-lung transplant recipients, 9 to 35% of heart transplant recipients, 22 to 29% of liver and pancreas transplant recipients, 8 to 32% of kidney transplant recipients, 50% of kidney-pancreas transplant recipients, and 22% of small-bowel transplant recipients (114), with the highest incidence seen in D+/R− patients. Finally, active HCMV infections have been associated with indirect effects, such as dysfunction or rejection of the transplanted organ, an increased risk for bacterial or fungal opportunistic infections, and accelerated atherosclerosis in heart transplant recipients (109). Among allogeneic bone marrow transplant (BMT) or hematopoietic stem cell transplant (HSCT) recipients, pneumonia and enteritis are the most common clinical manifestations of HCMV disease. In HCMV-seropositive recipients, active HCMV infections occur in 70 to 80% of patients; and in the absence of antiviral intervention, disease develops in 20 to 35% of those individuals, whereas active infections occur in only 15% of seronegative recipients of marrow from a seropositive donor (102). HCMV pneumonia remains associated with a significant risk of mortality, even when specific antiviral treatment is administered (18, 101). Gastrointestinal disease, alone or in association with pulmonary disease, is the second most common clinical manifestation of HCMV infections in that setting (85). In addition to AIDS patients and transplant recipients, HCMV infections have been associated with serious complications in other immunocompromised hosts, such as cancer patients, mostly those suffering from hematologic malignancies (48), and children with congenital primary immunodeficiencies (135). Finally, congenital HCMV infections can result in severe sequelae in newborns or during the first years of life (22).

Initiating highly active antiretroviral therapy in sub-Saharan Africa: an assessment of the revised World Health Organization scaling-up guidelines.

To assess the utility of the 2003 revised World Health Organization (WHO) criteria [initiating highly active antiretroviral therapy (HAART) in stage IV, in stage III plus CD4 cell count < 350 x 10(6) cells/l, or in stage I or II plus CD4 cell count < 200 x 10 cells/l] relative to other scenarios of HAART initiation. Progression to AIDS and death in 292 patients taking HAART and 974 not taking HAART in a South African institution in 1992-2001, stratifying patients by baseline CD4 cell count and WHO stage. HAART was associated with decreased AIDS [adjusted rate ratio [ARR], 0.16; 95% confidence interval (CI), 0.08-0.31) and death (ARR, 0.10; 95% CI, 0.06-0.18). Benefit of HAART was significant across all WHO stages plus CD4 cell counts. The greatest number of deaths averted was in stages IV [74.0/100 patient-years (PY); 95% CI, 50.2-84.5) and III (32.8/100 PY; 95% CI, 22.4-40.9). AIDS cases averted in stage III (22.0/100 PY; 95% CI, 6.1-26.9) were higher than in stage I and II with CD4 cell count < 200 x 10(6) cells/l (8.9/100 PY 95% CI, 5.6-13.3). Treatment initiation for symptomatic disease resulted in greater benefits than using any CD4 cell thresholds. Application of WHO criteria increased the treatment-eligible proportion from 44.5% to 56.7% (P < 0.05) but did not prevent more death (P > 0.05) than treating symptomatic disease. Implementation of the revised WHO guidelines in sub-Saharan Africa may result in a significantly increased number of individuals eligible for treatment but would not be as effective a strategy for preventing death as treating symptomatic disease.

Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models.

To estimate the net (i.e., overall) effect of highly active antiretroviral therapy (HAART) on time to acquired immunodeficiency syndrome (AIDS) or death, the authors used inverse probability-of-treatment weighted estimation of a marginal structural model, which can appropriately adjust for time-varying confounders affected by prior treatment or exposure. Human immunodeficiency virus (HIV)-positive men and women (n = 1,498) were followed in two ongoing cohort studies between 1995 and 2002. Sixty-one percent (n = 918) of the participants initiated HAART during 6,763 person-years of follow-up, and 382 developed AIDS or died. Strong confounding by indication for HAART was apparent; the unadjusted hazard ratio for AIDS or death was 0.98. The hazard ratio from a standard time-dependent Cox model that included time-varying CD4 cell count, HIV RNA level, and other time-varying and fixed covariates as regressors was 0.81 (95% confidence interval: 0.61, 1.07). In contrast, the hazard ratio from a marginal structural survival model was 0.54 (robust 95% confidence interval: 0.38, 0.78), suggesting a clinically meaningful net benefit of HAART. Standard Cox analysis failed to detect a clear net benefit, because it does not appropriately adjust for time-dependent covariates, such as HIV RNA level and CD4 cell count, that are simultaneously confounders and intermediate variables.