Generic and low dose antiretroviral therapy in adults and children: implication for scaling up treatment in resource limited settings

Although access to antiretroviral therapy (ART) for the treatment of HIV has increased during the last decade, many patients are still in need of treatment. With limited funds to provide ART to millions of patients worldwide, there is a need for alternative ways to scale up ART in resource limited settings. This review provides an overview of pharmacokinetic, safety and efficacy studies of generic and reduced dose ART. The production of generic ART has greatly influenced the decline in drug prices and the increased in ART access. Generic ART has good pharmacokinetic profile, safety and efficacy. Toxicity is however the main cause for ART discontinuation. Several dose reduction studies have shown adequate pharmacokinetic parameters and short term efficacy with reduced dose ART. Ethnicity may affect drug metabolism; several pharmacokinetic studies have confirmed higher plasma ART concentration in Asians. Randomized efficacy trial of reduced versus standard ART is warranted

Predictors of disease progression in HIV infection: a review

During the extended clinically latent period associated with Human Immunodeficiency Virus (HIV) infection the virus itself is far from latent. This phase of infection generally comes to an end with the development of symptomatic illness. Understanding the factors affecting disease progression can aid treatment commencement and therapeutic monitoring decisions. An example of this is the clear utility of CD4+ T-cell count and HIV-RNA for disease stage and progression assessment

Contraception in HIV-positive female adolescents

Sexual behavior of HIV-positive youths, whether infected perinatally, through risky behavior or other ways, is not substantially different from that of HIV-uninfected peers. Because of highly active antiretroviral therapy, increasing number of children, infected perinatally, are surviving into adolescence and are becoming sexually active and need reproductive health services. The objective of this article is to review the methods of contraception appropriate for HIV-positive adolescents with a special focus on hormonal contraceptives. Delaying the start of sexual life and the use of two methods thereafter, one of which is the male condom and the other a highly effective contraceptive method such as hormonal contraception or an intrauterine device, is currently the most effective option for those who desire simultaneous protection from both pregnancy and sexually transmitted diseases. Health care providers should be aware of the possible pharmacokinetic interactions between hormonal contraception and antiretrovirals. There is an urgent need for more information regarding metabolic outcomes of hormonal contraceptives, especially the effect of injectable progestins on bone metabolism, in HIV-positive adolescent girls

How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs?

The long-lived viral reservoir is a major obstacle to achieving a cure for HIV. Therapeutic strategies, such as early antiretroviral therapy (ART), may be a prerequisite to achieving long-term control of viral replication upon ART withdrawal

HIV DNA Reservoir Increases Risk for Cognitive Disorders in cART-Nave Patients

Objectives Cognitive impairment remains frequent in HIV, despite combination antiretroviral therapy (cART). Leading theories implicate peripheral monocyte HIV DNA reservoirs as a mechanism for spread of the virus to the brain. These reservoirs remain present despite cART. The objective of this study was to determine if the level of HIV DNA in CD14+ enriched monocytes predicted cognitive impairment and brain injury. Methods We enrolled 61 cART-naïve HIV-infected Thais in a prospective study and measured HIV DNA in CD14+ enriched monocyte samples in a blinded fashion. We determined HAND diagnoses by consensus panel and all participants underwent magnetic resonance spectroscopy (MRS) to measure markers of brain injury. Immune activation was measured via cytokines in cerebrospinal fluid (CSF). Results The mean (SD) age was 35 (6.9) years, CD4 T-lymphocyte count was 236 (139) and log10 plasma HIV RNA was 4.8 (0.73). Twenty-eight of 61 met HAND criteria. The log10 CD14+ HIV DNA was associated with HAND in unadjusted and adjusted models (p = 0.001). There was a 14.5 increased odds ratio for HAND per 1 log-value of HIV DNA (10-fold increase in copy number). Plasma CD14+ HIV DNA was associated with plasma and CSF neopterin (p = 0.023) and with MRS markers of neuronal injury (lower N-acetyl aspartate) and glial dysfunction (higher myoinositol) in multiple brain regions. Interpretation Reservoir burden of HIV DNA in monocyte-enriched (CD14+) peripheral blood cells increases risk for HAND in treatment-naïve HIV+ subjects and is directly associated with CSF immune activation and both brain injury and glial dysfunction by MRS

What can volunteer co-providers contribute to health systems? The role of people living with HIV in the Thai paediatric HIV programme

In Thailand people living with HIV (PLHIV) have played a major role in shaping policy and practice. They have acted as volunteer co-providers, although their potential in terms of paediatric service provision has seldom been explored from a health systems perspective. We describe the Thai paediatric HIV care system and use both demand- and supply-side perspectives to explore the impact, opportunities and challenges of PLHIV acting as volunteer co-providers. We employed qualitative methods to assess experiences and perceptions and triangulate stakeholder perspectives. Data were collected in Khon Kaen province, in the poorest Northeastern region of Thailand: three focus group discussions and two workshops (total participants n = 31) with co-providers and hospital staff; interviews with ART service-users (n = 35). Nationally, key informant interviews were conducted with policy actors (n = 20). Volunteer co-providers were found to be ideally placed to broker the link between clinic and communities for HIV infected children and played an important part in the vital psychosocial support component of HIV care. As co-providers they were recognized as having multiple roles linking and delivering services in clinics and communities. Clear emerging needs include strengthened coordination and training as well as strategies to support funding. Using motivated volunteers with a shared HIV status as co-providers for specific clinical services can contribute to strengthening health systems in Asia; they are critical players in delivering care (supply side) and being responsive to service-users needs (demand side). Co-providers blur the boundaries between these two spheres. Sustaining and optimising co-providers' contribution to health systems strengthening requires a health systems approach. Our findings help to guide policy makers and service providers on how to balance clinical priorities with psycho-social responsiveness and on how best to integrate the views and experience of volunteers into a holistic model of care

Monitoring the toxicity of antiretroviral therapy in resource limited settings: a prospective clinical trial cohort in Thailand

Background: One of the many challenges which come together with the implementation of antiretroviral therapy (ART) in settings with limited resources is the monitoring of toxicity. This monitoring increases costs of ART and strains resources. We therefore investigated the necessity for laboratory toxicity monitoring of ART in Thailand. Design, methods and participants: A prospective Thai cohort of 417 HIV-infected patients were enrolled in randomized clinical trials investigating ART. Time-dependent occurrence of grade III/IV abnormal laboratory values as defined by the AIDS Clinical Trial Group was analysed. Results: During a median observation period of 3.7 years (2.4-4.3) 142 grade III/IV toxicities occurred in 101 (24.2%) patients. Hepatic toxicity (n = 33, 7.9%), hypercholesterolaemia (n = 57, 13.7%), hypertriglyceridaemia (n = 26, 6.2%), anaemia (n = 16, 3.8%) and low platelet counts (n = 8, 1.9%) were frequently observed. Anaemia and low platelets occurred early and during the first 2 years of ART. Hepatic toxicity was seen early and throughout the observation period. Hypertriglyceridaemia and hypercholesterolaemia occurred throughout the observation period, and increased over time. Hypercreatininaemia and hyperglycaemia occurred once after 120 and 132 weeks. ART was changed or interrupted for grade III/IV hepatic toxicity, anaemia and hyperglycaemia only. The incidence rate for grade III/IV toxicity was between 5.56 (95% CI, 6.76-18.02) for low platelet counts and 41.18 (31.77-53.39) per 1000 patient years for hypercholesterolaemia. Antiretrovirals used were zidovudine, stavudine, lamivudine, zalcitabine, didanosine, efavirenz, saquinavir, ritonavir and indinavir. Conclusions: Grade III/IV toxicity is frequently observed in Thai patients treated with ART. The simple and inexpensive monitoring of ALT and haemoglobin could prevent most serious short-term toxicity. Long-term toxicity can be addressed with a yearly monitoring of triglycerides, cholesterol, glucose and creatinine if nephrotoxic drugs are use

The HIV treatment cascade in acutely infected people: informing global guidelines

Acute and early HIV (AHI) is a pivotal time during HIV infection, yet there remain major shortfalls in diagnosis, linkage to care, and antiretroviral therapy (ART) initiation during AHI. We introduce an AHI-specific cascade, review recent evidence pertaining to the unique challenges of AHI, and discuss strategies for improving individual and public health outcomes

Development of HIV with Drug Resistance after CD4 Cell Count—Guided Structured Treatment Interruptions in Patients Treated with Highly Active Antiretroviral Therapy after Dual—Nucleoside Analogue Treatment

Background. For patients with human immunodeficiency virus (HIV) infection, structured treatment interruption (STI) is an attractive alternative strategy to continuous treatment, particularly in resource-restrained settings, because it reduces both side effects and costs. One major concern, however, is the development of resistance to antiretroviral drugs that can occur during multiple cycles of starting and stopping therapy. Methods. HIV genotypic drug resistance was investigated in 20 HIV-infected Thai patients treated with highly active antiretroviral therapy (HAART) and CD4 cell count—guided STI after dual nucleoside reverse-transcriptase inhibitor (NRTI) treatment. Resistance was tested at the time of the switch from dual-NRTI treatment to HAART and when HAART was stopped during the last interruption. Results. After STI, one major drug-resistance mutation occurred (T215Y), and, in the 4 samples with preexisting major mutations (D67N [n = 2], K70R [n = 2], T215Y [n = 2], and T215I [n = 1]), the mutations disappeared. All mutations in the HIV protease gene were minor mutations already present, in most cases, before STI was started, and their frequency was not increased through STI, whereas the frequency of reverse-transcriptase gene mutations significantly decreased after the interruptions. After the 48-week study period, no patients had virological failure. Long-term follow-up (108 weeks) showed 1 case of virological failure in the STI arm and 1 in the continuous arm. No virological failure was seen in patients with major mutations. Conclusions. Major HIV drug-resistance mutations were not induced through CD4 cell count—guided treatment interruptions in HIV-infected patients successfully treated with HAART after dual-NRTI therap