Short-term toxicity assessment of combined use of zidovudine, lamivudine and lopinavir/ritonavir in vitro and in vivo.

INTRODUCTION: A combination of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV/r) is one of the most effective drugs for preventing mother-to-child transmission (PMTCT) of HIV. However, limited information is available regarding its systemic toxicity. This study aimed to investigate its potential toxicity. METHOD: An acute oral toxicity test was conducted to assess the potential acute toxicity of AZT + 3TC + LPV/r. Bacterial reverse mutation, mammalian erythrocyte micronucleus and mouse spermatogonia chromosomal aberration tests were conducted to assess its potential genotoxicity. A 28-day feeding test was conducted to assess the potential subacute toxicity. RESULTS: In mice, the LD50 of the AZT + 3TC + LPV/r mixture was greater than 2000 mg/kg body weight (BW). The rate of micronucleated polychromatic erythrocytes (PCEs) increased in a dose-dependent manner in mice (P < 0.01). After treatment with AZT + 3TC + LPV/r for 28 days, the BW gain of male and female rats in the high-dose group was lower than that in the control group (P < 0.05); the relative weights of the liver, kidney, spleen and brain increased (P < 0.05); and pathological abnormalities appeared in the thyroid and spleen of male and female rats in the high-dose group. The haemoglobin (HGB) and red blood cells (RBCs) count in male and female rats decreased, but the white blood cells (WBCs) and lymphocyte apoptosis rates in male and female rats in the high-dose group increased (P < 0.05). The total protein, albumin, cholesterol and blood glucose levels of male and female rats in the high-dose group were significantly decreased (P < 0.05). The alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine (Cr) and blood urea nitrogen (BUN) levels of male and female rats in the medium- and high-dose groups increased significantly (P < 0.05). CONCLUSION: The results suggest that AZT + 3TC + LPV/r may exhibit genotoxicity and subacute toxicity under experimental conditions.

A More Efficient Causal Mediator Model Without the No-Unmeasured-Confounder Assumption.

Mediator models have been developed primarily under the assumption of no-unmeasured-confounding. In many situations, this assumption is violated and may lead to the identification of mediator variables that actually are statistical artifacts. The rank preserving model (RPM) is an alternative approach to estimate controlled direct and mediator effects. It is based on the structural mean models framework and a no-effect-modifier assumption. The RPM assumes that unobserved confounders do not interact with treatment or mediators. This assumption is often more plausible to hold than the no-unmeasured-confounder assumption. So far, models using the no-effect-modifier assumption have been rarely used, which might be due to its low power and inefficiency in many scenarios. Here, a semi-parametric nonlinear extension, the nRPM, is proposed that overcomes this inefficiency using thin plate regression splines that both increase the predictive power of the model and decrease the misspecification present in many situations. In a simulation study, it is shown that the nRPM provides estimates that are robust against the violation of the no-effect-modifier assumption and that are substantively more efficient than those of the RPM. The model is illustrated using a data set on CD4 cell counts in a context of the human immunodeficiency virus (HIV).

Assessment of Nevirapine Prophylactic and Therapeutic Dosing Regimens for Neonates.

BACKGROUND: Nevirapine (NVP) is a key component of antiretroviral prophylaxis and treatment for neonates. We evaluated current World Health Organization (WHO) weight-band NVP prophylactic dosing recommendations and investigated optimal therapeutic NVP dosing for neonates. METHODS: The PHPT-5 study in Thailand assessed the efficacy of "Perinatal Antiretroviral Intensification" to prevent mother-to-child transmission of HIV in women with <8 weeks of antiretroviral treatment before delivery (NCT01511237). Infants received a 2-week course of zidovudine/lamivudine/NVP (NVP syrup/once daily: 2 mg/kg for 7 days; then 4 mg/kg for 7 days). Infant samples were assessed during the first 2 weeks of life. NVP population pharmacokinetics (PK) parameters were estimated using nonlinear mixed-effects models. Simulations were performed to estimate the probability of achieving target NVP trough concentrations for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L) using different infant dosing strategies. RESULTS: Sixty infants (55% male) were included. At birth, median (range) weight was 2.9 (2.3-3.6) kg. NVP concentrations were best described by a 1-compartment PK model. Infant weight and postnatal age influenced NVP PK parameters. Based on simulations for a 3-kg infant, ≥92% would have an NVP trough >0.1 mg/L after 48 hours through 2 weeks using the PHPT-5 and WHO-dosing regimens. For NVP-based therapy, a 6-mg/kg twice daily dose produced a trough >3.0 mg/L in 87% of infants at 48 hours and 80% at 2 weeks. CONCLUSION: WHO weight-band prophylactic guidelines achieved target concentrations. Starting NVP 6 mg/kg twice daily from birth is expected to achieve therapeutic concentrations during the first 2 weeks of life.

Protocolo de uso: zidovudina para tratamento do adulto com leucemia/linfoma associado ao vírus HTLV-1 / Use protocol: zidovudine for treatment of the adult with HTLV-1 virus-associated leukemia / lymphoma

O Protocolo de Uso da Zidovudina para Tratamento do Adulto com Leucemia/Linfoma Associado ao Vírus HTLV-1 foi idealizado pela Secretaria de Vigilância em Saúde/SVS/MS pela necessidade de se estabelecerem parâmetros sobre a leucemia/linfoma associada ao vírus HTLV-1 no Brasil e diretrizes nacionais para diagnóstico, tratamento e acompanhamento dos indivíduos com esta doença. De forma consoante a este objetivo, a Comissão Nacional de Tecnologias no SUS/CONITEC avaliou a incorporação da zidovudina para esta população de pacientes, e por meio do Registro de Deliberação N° 135, de 05 de agosto de 2015, recomendou favoravelmente pela sua inclusão no SUS para o tratamento do adulto com leucemia/linfoma associado ao vírus HTLV-1. O Relatório de Recomendação N° 173 de setembro/2015 traz o embasamento de evidências científicas e impacto orçamentário que nortearam a decisão. Em 2016, em sua 45° reunião, a CONITEC também deliberou favoravelmente pela inclusão na Tabela do SUS de procedimentos laboratoriais por técnicas de Western Blot e PCR em tempo real no diagnóstico de leucemia/linfoma de células T do adulto associado ao HTLV-1, permitindo assim, que tanto o diagnóstico preciso destes indivíduos quanto o tratamento, pudessem ser contemplados nesta diretriz de cuidado. Aos 05 (cinco) dias do mês de maio de 2016, reuniu-se a Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde -CONITEC, regulamentada pelo Decreto nº 7.646, de 21 de dezembro de 2011, e os membros presentes deliberaram por unanimidade recomendar a aprovação do Protocolo de uso da Zidovudina no tratamento da leucemia/linfoma de células T do adulto associado ao vírus HTLV-1. A Portaria Nº 54, de 18 de julho de 2016 - Aprova o Protocolo de Uso da Zidovudina para Tratamento do Adulto com Leucemia/Linfoma Associação ao Vírus HTLV-1.

[CLINICAL AND PHARMACOECONOMIC RESULTS OF THE USAGE OF VARIOUS HIV REVERSE TRANSCRIPTASE INHIBITORS IN THE SCHEMES OF ANTIRETROVIRAL THERAPY OF PATIENT RECEIVING THERAPY FOR THE CHRONIC HEPATITIS C VIRUS].

Efficacy, safety, and economical aspects of treatment with abacavir, zidovudine, stavudine, and phosphazide in the schemes of antiretroviral therapy of the HIV-infected patients receiving therapy for hepatitis C virus were tested. Clinical, immunological, and virologic efficacy of treatment and dynamics of hemoglobin, thrombocytes, and alanine aminotransferase as markers of common adverse events recorded at the start of the antiviral therapy of chronic hepatitis C and after 4, 8, 12, 24, 48 weeks of the treatment were evaluated. The usage of these drugs in the schemes of antiretroviral therapy exhibited efficacy, high tolerability and safety for all HIV reverse transcriptase inhibitors.

Point-of-care CD4 testing to inform selection of antiretroviral medications in south african antenatal clinics: a cost-effectiveness analysis.

BACKGROUND: Many prevention of mother-to-child HIV transmission (PMTCT) programs currently prioritize antiretroviral therapy (ART) for women with advanced HIV. Point-of-care (POC) CD4 assays may expedite the selection of three-drug ART instead of zidovudine, but are costlier than traditional laboratory assays. METHODS: We used validated models of HIV infection to simulate pregnant, HIV-infected women (mean age 26 years, gestational age 26 weeks) in a general antenatal clinic in South Africa, and their infants. We examined two strategies for CD4 testing after HIV diagnosis: laboratory (test rate: 96%, result-return rate: 87%, cost: $14) and POC (test rate: 99%, result-return rate: 95%, cost: $26). We modeled South African PMTCT guidelines during the study period (WHO "Option A"): antenatal zidovudine (CD4 ≤350/µL) or ART (CD4>350/µL). Outcomes included MTCT risk at weaning (age 6 months), maternal and pediatric life expectancy (LE), maternal and pediatric lifetime healthcare costs (2013 USD), and cost-effectiveness ($/life-year saved). RESULTS: In the base case, laboratory led to projected MTCT risks of 5.7%, undiscounted pediatric LE of 53.2 years, and undiscounted PMTCT plus pediatric lifetime costs of $1,070/infant. POC led to lower modeled MTCT risk (5.3%), greater pediatric LE (53.4 years) and lower PMTCT plus pediatric lifetime costs ($1,040/infant). Maternal outcomes following laboratory were similar to POC (LE: 21.2 years; lifetime costs: $23,860/person). Compared to laboratory, POC improved clinical outcomes and reduced healthcare costs. CONCLUSIONS: In antenatal clinics implementing Option A, the higher initial cost of a one-time POC CD4 assay will be offset by cost-savings from prevention of pediatric HIV infection.

Kericho CLinic-based ART Diagnostic Evaluation (CLADE): design, accrual, and baseline characteristics of a randomized controlled trial conducted in predominately rural, district-level, HIV clinics of Kenya.

BACKGROUND: Prospective clinical trial data regarding routine HIV-1 viral load (VL) monitoring of antiretroviral therapy (ART) in non-research clinics of Sub-Saharan Africa are needed for policy makers. METHODS: CLinic-based ART Diagnostic Evaluation (CLADE) is a randomized, controlled trial (RCT) evaluating feasibility, superiority, and cost-effectiveness of routine VL vs. standard of care (clinical and immunological) monitoring in adults initiating dual nucleoside reverse transcriptase inhibitor (NRTI)+non-NRTI ART. Participants were randomized (1:1) at 7 predominately rural, non-research, district-level clinics of western Kenya. Descriptive statistics present accrual patterns and baseline cohort characteristics. RESULTS: Over 15 months, 820 adults enrolled at 7 sites with 86-152 enrolled per site. Monthly site enrollment ranged from 2-92 participants. Full (100%) informed consent compliance was independently documented. Half (49.9%) had HIV diagnosed through voluntary counseling and testing. Study arms were similar: mostly females (57.6%) aged 37.6 (SD = 9.0) years with low CD4 (166 [SD = 106]) cells/m3). Notable proportions had WHO Stage III or IV disease (28.7%), BMI <18.5 kg/m2 (23.1%), and a history of tuberculosis (5.6%) or were receiving tuberculosis treatment (8.2%) at ART initiation. In the routine VL arm, 407/409 (99.5%) received baseline VL (234,577 SD = 151,055 copies/ml). All participants received lamivudine; 49.8% started zidovudine followed by 38.4% stavudine and 11.8% tenofovir; and, 64.4% received nevirapine as nNRTI (35.6% efavirenz). CONCLUSIONS: A RCT can be enrolled successfully in rural, non-research, resource limited, district-level clinics in western Kenya. Many adults presenting for ART have advanced HIV/AIDS, emphasizing the importance of universal HIV testing and linkage-to-care campaigns. TRIAL REGISTRATION: ClinicalTrials.gov NCT01791556.

Cost estimation of first-line antiretroviral therapy with zidovudine/stavudine as the nucleoside backbone in India: a pilot study.

BACKGROUND: In India, a zidovudine-based regimen is preferred as the first-line drug treatment for HIV, despite high rates of drug toxicity. This study estimates the treatment costs for HIV. METHODS: Eligible patients were enrolled from Antiretroviral Therapy Center, Christian Medical College, India. Baseline demographic and clinical characteristics, medical and nonmedical expenditure, and lost income were collected. RESULTS: Of 41 patients enrolled and followed for 6 months, HIV treatment toxicity and opportunistic infections were reported by 12 (29%) and 13 (31.7%) patients, respectively. The median total costs, direct costs, and out-of-pocket expenditure were Indian rupees (INR) 9418 (US$181), 8727 (US$168), and 7157 (US$138), respectively. Diagnostic tests accounted for 58% of the expenses. HIV treatment accounted for 34% of the median income earned INR 21 000 (US$404). Expenditure for treatment with toxicity was 44% higher than without toxicity. CONCLUSION: Current treatment is associated with toxicity, increasing treatment costs and imposing a significant economic burden.

The financial and service implications of splitting fixed-dose antiretroviral drugs - a case study.

In 2010/2011, regional commissioners withdrew payment for the fixed-dose combination Combivir, forcing a switch to component drugs. This was deemed clinically acceptable and annual savings of £44 k expected. We estimated the true costs of switching and examined patient outcomes. Information for 46 patients using Combivir was extracted from case notes for each clinical contact in the 12 months pre- and post-switch (clinician seen, tests, antiretrovirals). Post-switch care costs £93/patient more annually versus pre-switch (95% CI £424 to £609), yielding £4278/year more post-switch for all patients. Drug and pathology costs were more expensive post-switch and extra clinical visits required. None of these results were statistically significant. Forty-two per cent of patients switched directly or in the subsequent year to an alternative fixed-dose combination rather than generics. Costs in this group were significantly higher post-switch driven by drug cost. Six patients (13%) reported problems with the switch including confusion around dosing and new side effects. As less-expensive generic antiretroviral drugs become available, it may appear cheaper to switch from fixed-dose combinations to component drugs. However, the additional clinical costs involved may outweigh the initial cost savings of the drugs and switching may cause confusion for some patients, risking loss of adherence.

Antirretrovirais estavudina (d4t) 30mg e indinavir (idv) 400mg / Antiretroviral stavudine (d4t) 30mg and indinavir (idv) 400mg

INTRODUÇÃO: A partir da Nota Técnica nº 90/2012, de março de 2012, o Ministério da Saúde recomendou a substituição de estavudina (d4T) 30mg e indinavir (IDV) 400mg por outros antirretrovirais (ARV) da mesma classe terapêutica para todos os adultos ainda em uso destes medicamentos, e reitera a não indicação de ambos na terapia antirretroviral inicial. Após sua publicação, houve redução no número de pessoas em uso de d4T e IDV, permanecendo, entretanto, um contingente de pessoas com esquemas antirretrovirais estruturados com estes ARV. Conforme as diretrizes nacionais de tratamento antirretroviral, estes medicamentos não devem ser utilizados para estruturar o esquema antirretroviral inicial, em razão da existência de outras opções terapêuticas com melhor perfil de toxicidade. Assim, toda nova prescrição de tratamento com estavudina (d4T) e/ou indinavir (IDV) como primeiro esquema de tratamento para adultos, terá sua dispensação bloqueada pelo Sistema de Controle Logístico de Medicamento (SICLOM). Toda prescrição que mantenha d4T e/ou IDV para pacientes que já vinham em uso destes medicamentos no passado, terá que ser avaliada em relação a existência de outras opções de tratamento e aprovada pelas Câmaras Técnicas dos Estados ou pelo Ministério da Saúde. Aqueles que estão em uso destes medicamentos seu fornecimento será mantido por no máximo 6 (seis) meses após a publicação deste Relatório. Após este período, a dispensação destes medicamentos será bloqueada no SICLOM. Para pacientes que apresentam supressão viral completa (carga viral indetectável), sugere-se: a) substituir d4T por zidovudina (AZT), tenofovir (TDF), didanosina (ddI) ou abacavir (ABC); b) substituir IDV por lopinavir/ritonavir (LPV/r), atazanavir/ritonavir (ATV/r) ou fosamprenavir/ritonavir (FPV/r). Esta avaliação deve ser individualizada, considerando o histórico de tratamento antirretroviral e genotipagens anteriores.Pacientes que já fazem uso de IDV ou d4T e que estão em falha terapêutica, devem realizar teste de genotipagem e ter seu esquema estruturado conforme as diretrizes expressas no documento "Recomendações para Terapia Antirretroviral em Adultos Infectados pelo HIV" vigente no País. RECOMENDAÇÃO DA CONITEC: Os membros da CONITEC presentes na 24ª reunião do plenário realizada nos dias 09/04/2014 e 10/04/2014 recomendaram a exclusão da estavudina (d4T) 30mg e indinavir (IDV) 400mg na terapia antirretroviral inicial. DECISÃO: PORTARIA Nº 36, de 26 de setembro de 2014 - Torna pública a decisão de excluir os antirretrovirais estavudina (d4t) 30mg e indinavir (idv) 400mg no âmbito do Sistema Único de Saúde - SUS.

Robust joint modeling of longitudinal measurements and time to event data using normal/independent distributions: a Bayesian approach.

Joint modeling of longitudinal data and survival data has been used widely for analyzing AIDS clinical trials, where a biological marker such as CD4 count measurement can be an important predictor of survival. In most of these studies, a normal distribution is used for modeling longitudinal responses, which leads to vulnerable inference in the presence of outliers in longitudinal measurements. Powerful distributions for robust analysis are normal/independent distributions, which include univariate and multivariate versions of the Student's t, the slash and the contaminated normal distributions in addition to the normal. In this paper, a linear-mixed effects model with normal/independent distribution for both random effects and residuals and Cox's model for survival time are used. For estimation, a Bayesian approach using Markov Chain Monte Carlo is adopted. Some simulation studies are performed for illustration of the proposed method. Also, the method is illustrated on a real AIDS data set and the best model is selected using some criteria.

Impact of expanded access to combination antiretroviral therapy in pregnancy: results from a cohort study in Ukraine.

OBJECTIVE: To investigate the scale-up of antenatal combination antiretroviral therapy (cART) in Ukraine since this became part of the national policy for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV). METHODS: Data on 3535 HIV-positive pregnant women who were enrolled into the Ukraine European Collaborative Study in 2008-2010 were analysed. Factors associated with receipt of zidovudine monotherapy (AZTm) - rather than cART - and rates of mother-to-child transmission (MTCT) of HIV were investigated. FINDINGS: cART coverage increased significantly, from 22% of deliveries in 2008 to 61% of those in 2010. After adjusting for possible confounders, initiation of antenatal AZTm - rather than cART - was associated with cohabiting (versus being married; adjusted prevalence ratio, aPR: 1.09; 95% confidence interval, CI: 1.02-1.16), at least two previous live births (versus none; aPR: 1.22; 95% CI: 1.11-1.35) and a diagnosis of HIV infection during the first or second trimester (versus before pregnancy; aPR: 1.11; 95% CI: 1.03-1.20). The overall MTCT rate was 4.1% (95% CI: 3.4-4.9); 42% (49/116) of the transmissions were from the 8% (n = 238) of women without antenatal ART. Compared with AZTm, cART was associated with a 70% greater reduction in the risk of MTCT (adjusted odds ratio: 0.30; 95% CI: 0.16-0.56). CONCLUSION: Between 2008 and 2010, access to antenatal cART improved substantially in Ukraine, but implementation of the World Health Organization's Option-B policy was slow. For MTCT to be eliminated in Ukraine, improvements in the retention of women in HIV care and further roll-out of Option B are urgently needed.

Evaluating the cost-effectiveness of combination antiretroviral therapy for the prevention of mother-to-child transmission of HIV in Uganda.

OBJECTIVE: To model the cost-effectiveness in Uganda of combination antiretroviral therapy (ART) to prevent mother-to-child transmission of human immunodeficiency virus (HIV). METHODS: The cost-effectiveness of ART was evaluated on the assumption that ART reduces the risk of an HIV-positive pregnant woman transmitting HIV to her baby from 40% (when the woman is left untreated) to 25.8%, 17.4% and 3.8%, respectively, when the woman is given: (i) single-dose nevirapine (at an estimated total drug cost of 0.06 United States dollars [US$]); (ii) dual therapy with zidovudine and lamivudine for 7 weeks (at a total drug cost of US$ 15.63); or (iii) ART for 18 months (at a total annual cost of US$ 469.77). Lifetime ART (US$ 6883), recommended for pregnant women with < 350 CD4+ T lymphocytes per mm(3), was assumed to give the same reduction in transmission risk in each subsequent pregnancy. FINDINGS: Compared with single-dose nevirapine, dual therapy and no therapy, 18 months of ART averted 5.21, 3.22 and 8.58 disability-adjusted life years (DALYs), respectively, at a cost of US$ 46, US$ 99 and US$ 34 per DALY averted. The corresponding figures for lifetime ART are, respectively, 19.20, 11.87 and 31.60 DALYs averted, at a cost of US$ 205, US$ 354 and US$ 172 per DALY averted. CONCLUSION: In Uganda, ART appears highly cost-effective for the prevention of mother-to-child HIV transmission, even if continued over the patients' lifetimes. Given the additional public health benefits of ART, efforts to ensure that all HIV-positive pregnant women have access to lifelong ART should be intensified.

Costs and benefits of multidrug, multidose antiretroviral therapy for prevention of mother-to-child transmission of HIV in the Dominican Republic.

OBJECTIVE: To investigate whether costs of multidose antiretroviral regimens (MD-ARVs), including highly active antiretroviral therapy (HAART), for prevention of mother-to-child transmission (PMTCT) of HIV might be offset by savings gained from treating fewer perinatally acquired infections. METHODS: Rates of MTCT reported in the Dominican Republic among mother-infant pairs treated with single-dose nevirapine (SD-NVP; n=39) and MD-ARVs (n=91) for PMTCT were compared. Annual births to women infected with HIV were estimated from seroprevalence studies. Antiretroviral costs for both PMTCT and for HAART during the first 2 years of life (in cases of perinatal infection) were based on 2008 low-income country price estimates. RESULTS: Rates of MTCT were 3.3% and 15.4% for the MD-ARV and SD-NVP groups, respectively (P=0.02). Assuming that 5775 of 231 000 annual births (2.5%) were to HIV-positive women, it was estimated that 191 perinatally acquired infections would occur using MD-ARVs and 889 using SD-NVP. High costs of maternal MD-ARVs (HAART, US$914,760 versus SD-NVP, $1155) would be offset by lower 2-year HAART costs ($250,344 versus $1,168,272 for infants in the SD-NVP group) for the lower number of children with prenatally acquired infection (191 versus 889) associated with the use of MD-ARVs for PMTCT (net national saving $3168). CONCLUSION: Despite the high costs, use of MD-ARVs, such as HAART, for PMTCT offer societal savings because fewer perinatally acquired infections are anticipated to require treatment.

Records linkage of electronic databases for the assessment of adverse effects of antiretroviral therapy in sub-Saharan Africa.

PURPOSE: In 2009, the Ministry of Health and Social Services in Namibia decided to conduct a confirmatory assessment of the risk of anemia associated with zidovudine (AZT)-based highly active antiretroviral therapy (HAART) using records contained in three electronic databases. These records did not share a unique identifying number. The first step was to apply probabilistic record linkage methods to link records in the three databases. METHODS: Records of persons, aged 19-65 years, newly initiated on HAART between January 2007 and June 2008, were selected from a pharmacy electronic dispensing tool (EDT) and linked to an electronic medical records database (ePMS) and a laboratory database (MEDITECH). Using the paper-based clinical record as the gold standard, we measured the sensitivity of the starting HAART regimen, that is, proportion of AZT users in the clinical record correctly identified in electronic record, and specificity of severe anemia, that is, proportion of non-cases of severe anemia in the clinical records correctly identified in the electronic record. Kappa and intraclass correlation coefficients were used to determine reliability. RESULTS: A total of 12 358 records were selected from EDT. Seventy-six percent and 58% of EDT records were linked to ePMS and MEDITECH, respectively. The sensitivity of the starting HAART regimen was 98%, whereas specificity of severe anemia was 100%. The reliability scores for variables including weight, hemoglobin, and CD4 counts were moderate to perfect and ranged from 0.59 to 0.99. CONCLUSION: Probabilistic record linkage methods were effective for records linkage in this sub-Saharan African setting.

Therapy for HIV: past, present, and future.

Initial therapies for HIV infection comprised nucleoside analogues, but as single or dual agents, they failed to prevent disease progression. When a new class of drug was introduced, the protease inhibitors, an effective triple therapy became possible-namely, highly active antiretroviral therapy, or HAART. HAART reduced viral replication almost completely and enabled immune system recovery. The probability of classical infections and tumors attributed to HIV were dramatically reduced, and life expectancy correspondingly increased. The initial disadvantages of HAART included the need for strict adherence to prevent drug resistance, the cost that initially precluded their widespread use in the developing world, and the short- and long-term side effects. One of the most disabling long-term complications was HIV lipodystrophy, which in extreme cases lead to severe peripheral fat wasting and central fat gain. In recent years, many of these disadvantages have been addressed: Once-daily drug combinations improve adherence; global access to HAART has been markedly improved; and new drugs enable patients to avoid many of the initial side effects. Future research will determine at what CD4 count HAART should be initiated, and new approaches such as immunotherapeutic HIV vaccines are being tested with the aim to delay or obviate the need for antiretroviral drugs.