Sunday, September 30, 2012

Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV

Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort.

Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy is unclear. The authors estimated the effect of prophylaxis after antiretroviral therapy initiation in adults. Participants in their observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug antiretroviral therapy with CD4 counts lower than 200 cells per muL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. They estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. 3179 participants contributed 14 214 years of follow-up (8128 [57%] person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, body-mass index, and previous WHO stage 3 or 4 events on antiretroviral therapy. Present prophylaxis significantly reduced mortality (odds ratio 0.65, 95% CI 0.50-0.85; p=0.001). Mortality risk reduction on antiretroviral therapy was substantial to 12 weeks (0.41, 0.27-0.65), sustained from 12-72 weeks (0.56, 0.37-0.86), but not evident subsequently (0.96, 0.63-1.45; heterogeneity p=0.02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0.74, 0.63-0.88; p=0.0005), an effect that was maintained with time, but the authors observed no effect on new WHO stage 4 events (0.86, 0.69-1.07; p=0.17), CD4 cell count (difference vs non-users, -3 cells per muL [-12 to 6]; p=0.50), or body-mass index (difference vs non-users, -0.04 kg/m(2) [-0.20 to 0.13); p=0.68]. These results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination antiretroviral therapy in Africa.

Editors’ note: DART delivers again, this time with data supporting the use of cotrimoxasole (trimethoprim-sulfamethoxasole) at the start of antiretroviral therapy in resource-limited settings, if it hasn’t been started before. Co-trimoxasole is off-patent, low-cost, simple to take (once daily), safe, and tolerable. First-year mortality on antiretroviral treatment in sub-Saharan Africa ranges from 8 to 26%, most in the first 3 to 6 months. Mortality in this large study was halved in the first 72 weeks on antiretroviral treatment with daily cotrimoxasole prophylaxis. The mortality reduction was greatest in the first 12 weeks and then was sustained out to 72 weeks for both patients with CD4 counts under 200 and over 200. The effects on malaria in the Uganda patients was sustained out past 72 weeks. Clearly, starting on antiretroviral treatment is not reason to stop or not to start cotrimoxasole prophylaxis. Whether cotrimoxasole works by helping reduce immune activation before antiretroviral treatment starts to kick in or acts through another mechanism is unknown but these data support the World Health Organisation recommendation to start or continue cotrimoxasole prophylaxis when antiretroviral treatment is started. There is now justification for continuing it for at least 72 weeks.

Nonoccupational HIV post-exposure prophylaxis

Nonoccupational HIV post-exposure prophylaxis: a 10-year retrospective analysis.

The authors conducted a retrospective analysis of administration of non-occupational HIV post-exposure prophylaxis in a single centre where tracing and testing of the source of exposure were carried out systematically over a 10-year period. Files of all non-occupational HIV post-exposure prophylaxis requests between 1998 and 2007 were reviewed. Characteristics of the exposed and source patients, the type of exposure, and clinical and serological outcomes were analysed. Request for non-occupational HIV post-exposure prophylaxis increased by 850% over 10 years. Among 910 events, 58% were heterosexual exposures, 15% homosexual exposures, 6% sexual assaults and 20% nonsexual exposures. In 208 events (23%), the source was reported to be HIV positive. In the remaining cases, active source tracing enabled 298 HIV tests to be performed (42%) and identified 11 HIV infections (3.7%). Non-occupational HIV post-exposure prophylaxis was able to be avoided or interrupted in 31% of 910 events when the source tested negative. Of 710 patients who started non-occupational HIV post-exposure prophylaxis, 396 (56%) reported side effects, among whom 39 (5%) had to interrupt treatment. There were two HIV seroconversions, and neither was attributed to non-occupational HIV post-exposure prophylaxis failure. Non-occupational HIV post-exposure prophylaxis requests increased over time. HIV testing of the source person avoided non-occupational HIV post-exposure prophylaxis in 31% of events and was therefore paramount in the management of potential HIV exposures. Furthermore, it allowed active screening of populations potentially at risk for undiagnosed HIV infection, as shown by the increased HIV prevalence in these groups (3.7%) compared with a prevalence of 0.3% in Switzerland as a whole.

Editors’ note: Conducting a randomised controlled trial to determine the efficacy of n-PEP (nonoccupational post-exposure prophylaxis) is not possible for ethical reasons but animal studies, prevention of mother-to-child transmission, and case-control studies after needle stick injuries support a protective effect. This large study conducted in Lausanne, Switzerland over 10 years found that the best way to prevent unnecessary exposure to antiretroviral drugs for 28 days (64% of people reported side effects, treatment costs are charged directly to the patient who gets partially reimbursed through insurance) was to contact the source and encourage them to learn their HIV status. Interestingly, police officers were significantly more likely to be able do this than people who were not police officers (57 vs. 32%; p<0.001).>

programmes was associated with a lower incidence of HIV

Injecting Drug Use

Optimal provision of needle and syringe programmes for injecting drug users: A systematic review.

The introduction of needle and syringe programmes (NSPs) during the 1980s is credited with averting an HIV epidemic in the United Kingdom and Australia, but hepatitis C (HCV) incidence continues to rise among people injecting drugs. Needle and syringe programmes incorporating additional harm reduction strategies have been highlighted as an approach that may influence HCV incidence. This systematic review sought to determine which approaches to the organisation and delivery of needle and syringe programmes are effective. Fifteen databases were searched for studies published since 1990. Two reviewers screened all titles and abstracts, and data extraction and quality assessment of individual studies were undertaken independently by one reviewer and checked for accuracy by a second. Sixteen studies met the criteria for inclusion. Based on 11 studies there was no evidence of an impact of different needle and syringe programmes settings or syringe dispensation policies on drug injecting behaviours, but mobile van sites and vending machines appeared to attract younger people who inject drugs and people who inject drugs with higher risk profiles. Two studies of interventions aimed at encouraging people who inject drugs to enter drug treatment reported limited effects, but one study found that the combination of methadone treatment and full participation in needle and syringe programmes was associated with a lower incidence of HIV and HCV. In addition, one study indicated that hospital-based programmes may improve access to health care services among people who inject drugs. Currently, it is difficult to draw conclusions on 'what works best' within the range of harm reduction services available to people who inject drugs. Further studies are required which have a stated aim of evaluating how different approaches to the organisation and delivery needle and syringe programmes influence on effectiveness.


Editors’ note: This systematic review of existing studies found a paucity of evidence on the impact of organising needle-syringe programmes in different ways. The majority of evaluated programmes had combined needle-syringe distribution with other harm reduction strategies such as outreach, distribution of materials, and testing for blood borne viruses. The settings in which the services were offered varied. However, it was not possible to determine the effects of the additional components nor of different settings on drug injecting behaviours and the incidence and prevalence of blood borne viruses due to limitations in study design. The majority of studies were observational in nature and only four were randomised controlled trials. However, a variety of non-randomised designs for evaluation of public health interventions can be used to compare different service delivery models. It makes common sense that ‘one-stop shopping’ for HIV testing, needles/syringes, low threshold methadone, social support, and primary health care would best meet the needs of people who inject drugs. Key informant interviews, focus groups, and web surveys can be used to gather information on what service users think would most likely work for themselves and others. The principles of good participatory practice in biomedical HIV prevention trials of respect, transparency, integrity, and accountability are equally applicable to the design of services that will reduce risk and improve the health of people who inject drugs (cf UNAIDS/AVAC Good participatory practice guidelines in biomedical HIV

Duration of Pneumonia and Diarrheal Episodes in HIV-Infected Children

Short-Term Micronutrient Supplementation Reduces the Duration of Pneumonia and Diarrheal Episodes in HIV-Infected Children

The duration of pneumonia and of diarrhoea is reported to be longer in HIV-infected than in uninfected children. The authors assessed the effect of a multi-micronutrient supplement on the duration of hospitalization in HIV-infected children. In a double-blind, randomized trial, HIV-infected children (4-24 mo) who were hospitalized with diarrhoea or pneumonia were enrolled (n = 118) and given a daily dose of a multi-micronutrient supplement (containing vitamins A, B complex, C, D, E, and folic acid, as well as copper, iron, and zinc at levels based on recommended daily allowances) or a placebo until discharge from the hospital. Children's weights and heights were measured after enrolment and micronutrient concentrations were measured before discharge. On recovery from diarrhoea or pneumonia, the children were discharged and the duration of hospitalization was noted. Anthropometric indices and micronutrient concentrations did not differ between children who received supplements and those who received placebos. Overall, the duration of hospitalization was shorter (P <> (7.3 +/- 3.9 days) (mean +/- SD) than in children who were receiving placebos (9.0 +/- 4.9); this was independent of admission diagnosis. In children admitted with diarrhoea, the duration of hospitalization was 1.6 days (19%) shorter among children receiving supplements than in those receiving placebos, and hospitalization for pneumonia was 1.9 days (20%) shorter among children receiving supplements. Short-term multi-micronutrient supplementation significantly reduced the duration of pneumonia or diarrhoea in HIV-infected children who were not yet receiving antiretroviral therapy and who remained alive during hospitalization.


Editors’ note: The role of micronutrient deficiency in HIV infection is not well understood and micronutrient supplementation remains controversial. Further, both pneumonia and diarrhoea can cause micronutrient deficiencies. This study of 118 children with HIV infection admitted to hospital for pneumonia or diarrhoea and randomised to receive a micronutrient supplement or placebo found a significantly shorter duration of hospitalisation for those children receiving the supplement. This both decreased their chance of a hospital-acquired infection and freed up a hospital bed earlier for another child. Unfortunately, no baseline micronutrient levels were established before the supplements began so it is impossible to know to what extent the children were micronutrient deficient in the first place. This area clearly deserves further study to confirm these findings. Even more so, it would be useful to determine whether supplementation might reduce the incidence of diarrhoea and pneumonia, both of which are more common in children with HIV infection.

Sexual behaviour

Sexual behaviour

The objective of the study was to explore the relative contribution of secular trends and public health policies to changes in sexual behaviour. Three random probability surveys of the sexual behaviour of people aged 18-69 years were conducted in 1970, 1992 and 2006 in France. Data of the 2006 survey (n = 12 364) were compared with those from two surveys carried out in 1970 (n = 2625) and 1992(n = 20 055). Over the last decades, median age at first intercourse has decreased by 4 years for women (22.0 in the 1930s vs. 17.6 in the 2000s) and 1 year for men (18.1 vs. 17.2). Lifetime number of sexual partners increased for women (1.8 in 1970 vs. 4.4 in 2006), but not for men (11.8 vs. 11.6). At the same time, the proportion of respondents, especially women, who reported nonpenetrative sexual practices and considered sexual intercourse essential to well being was on the increase. These changes are mainly attributed to an increase in women's social status. A marked increase in condom use was observed following the first HIV prevention campaigns in the 1980s. Public health interventions that are synergistic with trends in social norms are likely to be more effective than those that run counter to them. In France, sexual health and HIV prevention policies aimed at harm limitation appear to have chimed with secular trends. The evidence of greater diversification of sexual practices offers potential to increase the range of safer sex messages used in public health interventions.

For abstract access click here:
Editors’ note: This fascinating retrospective analysis of trends in sexual behaviours in France over almost three quarters of a century reveals dramatic changes, particularly among women. The gap between age at first sex between men and women has fallen from 4 years to 4 months while use of any contraceptive method rose steadily from 37% in the early 1940s to 92.9% by 2005. Lifetime numbers of sexual partners remained stable for men of all ages but increased for women from 1.8 in 1970 to 4.4 in 2006. Condom use at first sex was below 10% for those starting sex before 1960 but rose to more than 80% by the mid-1990s. Although it is difficult to sort out whether changes in sexual behaviour were the result of public health interventions or the result of changes in the broader social context, the fact that condom use at first sex became normalised was likely the result of a focus on the routinization of condom use in HIV public education campaigns. From the HIV perspective, the findings about increasing nonpenetrative sexual practices are striking: lifetime reported masturbation increased three-fold for women aged 20-49 years from 19% in 1970 to 62% in 2006 and for men from 71% to 92%. Lifetime experience of oral sex increased from 51% to 91% for women and 55% to 94% for men. This suggests that the UNAIDS term ‘abstinence from penetrative sex’ as an HIV prevention strategy could have public health significance equivalent to condom promotion among young people in some settings.

Saturday, September 29, 2012

HIV infection: a systematic review and meta-analysisA

Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis

In patients with HIV-1 infection who are starting combination antiretroviral therapy, the incidence of immune reconstitution inflammatory syndrome (IRIS) is not well defined. The authors did a meta-analysis to establish the incidence and lethality of the syndrome in patients with a range of previously diagnosed opportunistic infections, and examined the relation between occurrence and the degree of immunodeficiency. Systematic review identified 54 cohort studies of 13 103 patients starting ART, of whom 1699 developed IRIS. They calculated pooled cumulative incidences with 95% credibility intervals (CrI) by Bayesian methods and did a random-effects metaregression to analyse the relation between CD4 cell count and incidence of IRIS. In patients with previously diagnosed AIDS-defining illnesses, IRIS developed in 37.7% (95% CrI 26.6-49.4) of those with cytomegalovirus retinitis, 19.5% (6.7-44.8) of those with cryptococcal meningitis, 15.7% (9.7-24.5) of those with tuberculosis, 16.7% (2.3-50.7) of those with progressive multifocal leukoencephalopathy, and 6.4% (1.2-24.7) of those with Kaposi's sarcoma, and 12.2% (6.8-19.6) of those with herpes zoster. 16.1% (11.1-22.9) of unselected patients starting antiretroviral therapy developed any type of IRIS. 4.5% (2.1-8.6) of patients with any type of IRIS died, 3.2% (0.7-9.2) of those with tuberculosis-associated IRIS died, and 20.8% (5.0-52.7) of those with cryptococcal meningitis died. Metaregression analyses showed that the risk of IRIS is associated with CD4 cell count at the start of antiretroviral therapy, with a high risk in patients with fewer than 50 cells per muL. Occurrence of IRIS might therefore be reduced by initiation of antiretroviral therapy before immunodeficiency becomes advanced.

For full text access click here :

Editors’ note: Antiretroviral therapy gradually restores immune responses by suppressing HIV-1 replication and increasing CD4+ counts. Some people develop an immune reconstitution inflammatory syndrome (IRIS) when they start antiretroviral therapy either because their immune system develops an exaggerated activation against a persistent antigen (called paradoxical IRIS) or viable pathogens (called unmasking IRIS). This systematic review suggests that IRIS is more likely to occur when CD4 cell counts are low and in those who have a past history of cytomegalovirus retinitis, cryptococcal meningitis, and tuberculosis. The study of IRIS could teach us more about the immune system as IRIS appears to result from exaggerated and deregulated immune responses that vary depending on the associated pathogen. Little is known about treating IRIS although corticosteroids may be effective in extreme cases. What is clear is that the higher the CD4 count at initiation of antiretroviral treatment, the lower the risk of opportunistic infections and the lower the risk of IRIS.

Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults.

Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults.

Siegfried N, Uthman OA, Rutherford GW. Cochrane Database Syst Rev. 2010;3:CD008272

According to consensus, initiation of therapy is best based on CD4 cell count, a marker of immune status, rather than on viral load, a marker of virologic replication. For patients with advanced symptoms, treatment should be started regardless of CD4 count. However, the point during the course of HIV infection at which antiretroviral therapy is best initiated in asymptomatic patients remains unclear. Guidelines issued by various agencies provide different initiation recommendations according to resource availability. This can be confusing for clinicians and policy-makers when determining the best time to initiate therapy. Optimizing the initiation of antiretroviral therapy is clearly complex and must, therefore, be balanced between individual and broader public health needs. The objective of the study was to assess the evidence for the optimal time to initiate antiretroviral therapy in treatment-naive, asymptomatic, HIV-infected adults. The authors formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published,unpublished, in press, and in progress). In August 2009, they searched the following electronic journal and trial databases: MEDLINE, EMBASE, and CENTRAL. They also searched the electronic conference database of NLM Gateway, individual conference proceedings and prospective trials registers. They contacted researchers and relevant organizations and checked reference lists of all included studies. Randomized controlled trials that compared the effect of antiretroviral therapy consisting of three drugs initiated early in the disease at high CD4 counts as defined by the trial were selected. Early initiation could be at levels of 201-350, 351-500, or >500 cells/microL, with the comparison group initiating antiretroviral therapy at CD4 counts below 200 x 10(6) cells/microL or as defined by the trial. Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Where clinically meaningful to do so, they meta-analysed dichotomous outcomes using the relative risk (RR) and report the 95% confidence intervals (95% CIs). They found that one completed trial (N = 816) and one sub-group (N = 249) of a larger trial met inclusion criteria. They combined the mortality data for both trials comparing initiating antiretroviral therapy at CD4 levels at 350 cells/microL or between 200 and 350 cells/microL with deferring initiation of antiretroviral therapy to CD4 levels of 250 cells/microL or 200 cells/microL. There was a statistically significant reduction in death when starting antiretroviral therapy at higher CD4 counts. Risk of death was reduced by 74% (RR = 0.26; 95% CI: 0.11, 0.62; P = 0.002). Risk of tuberculosis was reduced by 50% in the groups starting antiretroviral therapy early; this was not statistically significant, with the reduction as much as 74% or an increased risk of up to 12% (RR = 0.54; 95% CI:0.26, 1.12; P = 0.01). Starting antiretroviral therapy at enrolment (when participants had CD4 counts of 350 cells/microL) rather than deferring to starting at a CD4 count of 250 cells/microL reduced the risk of disease progression by 70%; this was not statistically significant, with the reduction in risk as much as 97% or an increased risk of up to 185% (RR = 0.30; 95% CI: 0.03, 2.85; P = 0.29).One randomised controlled clinical trial found no statistically significant difference in the number of independent Grade 3 or 4 adverse events occurring in the early and standard antiretroviral therapy groups when the authors conducted an intention-to-treat analysis (RR = 1.72; 95% CI: 0.98, 3.03; P = .06). However, when analyzing only participants who actually commenced antiretroviral therapy in the deferred group (n = 160), the trial authors report a statistically significant increase in the incidence of zidovudine-related anaemia (8.1%) compared with those in the early initiation group (3.4%) (RR = 0.42; 95% CI: 0.20, 0.88; P = 0.02). The authors conclude that there is evidence of moderate quality that initiating antiretroviral therapy at CD4 levels higher than 200 or 250 cells/microL reduces mortality rates in asymptomatic, antiretroviral therapy-naive, HIV-infected people. Practitioners and policy-makers may consider initiating antiretroviral therapy at levels

Intellectual Property: patent pools

Intellectual Property: patent pools

The UNITAID Patent Pool Initiative: Bringing Patents Together for the Common Good.

Developing and delivering appropriate, affordable, well-adapted medicines for HIV remains an urgent challenge: as first-line therapies fail, increasing numbers of people require costly second-line therapy; one-third of antiretrovirals are not available in paediatric formulations; and certain key first- and second-line triple fixed-dose combinations do not exist or sufficient suppliers are lacking. UNITAID aims to help solve these problems through an innovative initiative for the collective management of intellectual property rights - a patent pool for HIV medicines. The idea behind a patent pool is that patent holders - companies, governments, researchers or universities - voluntarily offer, under certain conditions, the intellectual property related to their inventions to the patent pool. Any company that wants to use the intellectual property to produce or develop medicines can seek a license from the pool against the payment of royalties, and may then produce the medicines for use in developing countries (conditional upon meeting agreed quality standards). The patent pool will be a voluntary mechanism, meaning its success will largely depend on the willingness of pharmaceutical companies to participate and commit their intellectual property to the pool. Generic producers must also be willing to cooperate. The pool has the potential to provide benefits to all.

For full text access click here:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842943/
Editors’ note: UNITAID, launched at the UN General Assembly in September 2006 by Brazil, Chile, France, Norway, and the United Kingdom, is an innovative financing mechanism that has expanded to include more than 29 countries and the Bill and Melinda Gates Foundation. Some are providing multi-year budgetary contributions while others have placed a solidarity tax on airline tickets. A full plane from Paris to New York raises enough money to cover a year of antiretroviral treatment for 60 HIV-positive children. In addition to dedicating at least 85% of its spending on products for low-income countries, UNITAID is committed to a pro-health approach to intellectual property. The concept of patent pools is very timely now. Fixed dose combinations of the new WHO recommended first line of tenofovir, lamivudine, and nevirapine or efavirenz, do not exist or are limited in supply. Affordable second line drugs are urgently needed for patients failing first line therapy and a third of antiretroviral drugs are not available in paediatric formulation. Patent terms are normally 20 years. Patent pools have worked, for example, in agriculture, aeronautics, and information technology when relevant patents for a process are owned by many different entities. They reward pharmaceutical companies for their investment in research and development, give them a reputational boost, reduce transaction costs associated with negotiating individual license and price reductions, and avert the risk of compulsory licensing of their products. Patent pools provide generic companies access to intellectual property more easily and quickly and they ensure faster access to better, more affordable antiretroviral treatment for patients in low-income countries. Under the World Trade Organisation (WTO) Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS), governments can and do override patents to meet public health needs. However, a less complex and more timely process would be a voluntary patent pool. It is time to step up to the plate!

increased sexual risk behaviour in Kenyan female sex workers.

Treatment with antiretroviral therapy is not associated with increased sexual risk behaviour in Kenyan female sex workers.

The objective of this study was to test the hypothesis that sexual risk behaviour would increase following initiation of antiretroviral therapy. A prospective cohort of Kenyan female sex workers were recruited in Mombasa, Kenya between 1993-2008. Eight hundred and ninety-eight women contributed HIV-1-seropositive follow-up visits, of whom 129 initiated antiretroviral therapy. Beginning in March 2004, antiretroviral therapy was provided to women qualifying for treatment according to Kenyan National Guidelines. Participants received sexual risk reduction education and free condoms at every visit. Main outcome measures included unprotected intercourse, abstinence, 100% condom use, number of sexual partners, and frequency of sex. Outcomes were evaluated at monthly follow-up visits using a 1-week recall interval. Compared with non-antiretroviral therapy-exposed follow-up, visits following antiretroviral therapy initiation were not associated with an increase in unprotected sex [adjusted odds ratio (AOR) 0.86, 95% confidence interval (CI) 0.62-1.19, P = 0.4]. There was a nonsignificant decrease in abstinence (AOR 0.81, 95% CI 0.65-1.01, P = 0.07), which was offset by a substantial increase in 100% condom use (AOR 1.54, 95% CI 1.07-2.20, P = 0.02). Numbers of sex partners and frequency of sex were similar before versus after starting antiretroviral therapy. A trend for decreased sexually transmitted infections following antiretroviral therapy initiation provides additional support for the validity of the self-reported behavioural outcomes (AOR 0.67, 95% CI 0.44-1.02, P = 0.06). In the setting of ongoing risk reduction education and provision of free condoms, initiation of antiretroviral therapy was not associated with increased sexual risk behaviour in this cohort of Kenyan female sex workers.

For abstract access click here:
Editors’ note: This finding of no risk enhancement/risk compensation behaviour in these Nairobi sex workers after they started on antiretroviral treatment stands on firm ground. In fact, a highly significant increase of more than 50% in consistent condom use was reported. This prospective study collected considerable amounts of data on sexual behaviour before antiretroviral therapy was initiated, followed women for a median of more than 2 years after treatment started, had similar intensity risk-reduction counselling before and after treatment began, and was large enough to control for multiple potential confounding factors. As well, biological indicators such as the presence of sperm in genital secretions indicating recent unprotected sexual intercourse and incident sexually transmitted infections suggesting inconsistent condom use helped validate self-reports of sexual behaviour. There has been concern that the benefits of treatment scale-up in decreasing viral loads and reducing HIV transmission might be shot out of the water by increased sexual risk taking as people feel better but this study of Nairobi sex workers confirms findings from the majority of African studies demonstrating no increase in risk behaviour when people start on antiretroviral therapy.

increased sexual risk behaviour in Kenyan female sex workers.

Treatment with antiretroviral therapy is not associated with increased sexual risk behaviour in Kenyan female sex workers.

The objective of this study was to test the hypothesis that sexual risk behaviour would increase following initiation of antiretroviral therapy. A prospective cohort of Kenyan female sex workers were recruited in Mombasa, Kenya between 1993-2008. Eight hundred and ninety-eight women contributed HIV-1-seropositive follow-up visits, of whom 129 initiated antiretroviral therapy. Beginning in March 2004, antiretroviral therapy was provided to women qualifying for treatment according to Kenyan National Guidelines. Participants received sexual risk reduction education and free condoms at every visit. Main outcome measures included unprotected intercourse, abstinence, 100% condom use, number of sexual partners, and frequency of sex. Outcomes were evaluated at monthly follow-up visits using a 1-week recall interval. Compared with non-antiretroviral therapy-exposed follow-up, visits following antiretroviral therapy initiation were not associated with an increase in unprotected sex [adjusted odds ratio (AOR) 0.86, 95% confidence interval (CI) 0.62-1.19, P = 0.4]. There was a nonsignificant decrease in abstinence (AOR 0.81, 95% CI 0.65-1.01, P = 0.07), which was offset by a substantial increase in 100% condom use (AOR 1.54, 95% CI 1.07-2.20, P = 0.02). Numbers of sex partners and frequency of sex were similar before versus after starting antiretroviral therapy. A trend for decreased sexually transmitted infections following antiretroviral therapy initiation provides additional support for the validity of the self-reported behavioural outcomes (AOR 0.67, 95% CI 0.44-1.02, P = 0.06). In the setting of ongoing risk reduction education and provision of free condoms, initiation of antiretroviral therapy was not associated with increased sexual risk behaviour in this cohort of Kenyan female sex workers.

For abstract access click here:
Editors’ note: This finding of no risk enhancement/risk compensation behaviour in these Nairobi sex workers after they started on antiretroviral treatment stands on firm ground. In fact, a highly significant increase of more than 50% in consistent condom use was reported. This prospective study collected considerable amounts of data on sexual behaviour before antiretroviral therapy was initiated, followed women for a median of more than 2 years after treatment started, had similar intensity risk-reduction counselling before and after treatment began, and was large enough to control for multiple potential confounding factors. As well, biological indicators such as the presence of sperm in genital secretions indicating recent unprotected sexual intercourse and incident sexually transmitted infections suggesting inconsistent condom use helped validate self-reports of sexual behaviour. There has been concern that the benefits of treatment scale-up in decreasing viral loads and reducing HIV transmission might be shot out of the water by increased sexual risk taking as people feel better but this study of Nairobi sex workers confirms findings from the majority of African studies demonstrating no increase in risk behaviour when people start on antiretroviral therapy.

compound sex workers' individual risk for HIV

Sex Work

Sex work and the 2010 FIFA World Cup: time for public health imperatives to prevail.

Sex work is receiving increased attention in southern Africa. In the context of South Africa's intense preparation for hosting the 2010 FIFA World Cup, anxiety over HIV transmission in the context of sex work has sparked debate on the most appropriate legal response to this industry. Drawing on existing literature, the authors highlight the increased vulnerability of sex workers in the context of the HIV pandemic in southern Africa. They argue that laws that criminalise sex work not only compound sex workers' individual risk for HIV, but also compromise broader public health goals. International sporting events are thought to increase demand for paid sex and, particularly in countries with hyper-endemic HIV such as South Africa, likely to foster increased HIV transmission through unprotected sex. The 2010 FIFA World Cup presents a strategic opportunity for South Africa to respond to the challenges that the sex industry poses in a strategic and rights-based manner. Public health goals and growing evidence on HIV prevention suggest that sex work is best approached in a context where it is decriminalised and where sex workers are empowered. In short, the authors argue for a moratorium on the enforcement of laws that persecute and victimise sex workers during the World Cup period.

For full text access click here:
Editors’ Note: With kick-off for the 2010 FIFA World Cup not far off, South Africa has clearly missed an opportunity to proactively reform its sex work laws as Germany did in 2002, four years before it hosted the FIFA World Cup. South Africa has been reviewing its sexual offenses legislation and considering reform of sex work laws for almost a decade but the South African Law Reform Commission’s recommendations on law reform and sex work are not expected until 2011. If Parliament sanctions a moratorium on enforcement of the laws that persecute and victimise sex workers during the World Cup and if public health authorities ensure distribution of free male and female condoms and raise awareness about safer sex and sex workers rights, the immediate benefit would be reduced HIV transmission. But these actions could also inform longer-term decriminalisation strategies in South Africa and other countries in the region, strategies that empower sex workers and make their working conditions safer. South Africa is the country with the greatest number of people living with HIV in the world. Securing the long-term health of its own citizens and of the people who visit it requires progressive public health initiatives and changes in legal frameworks. Go South Africa go!

Friday, September 28, 2012

Millennium Development Goals

Millennium Development Goals

Maternal mortality for 181 countries, 1980-2008: a systematic analysis of progress towards Millennium Development Goal 5.

Maternal mortality remains a major challenge to health systems worldwide. Reliable information about the rates and trends in maternal mortality is essential for resource mobilisation, and for planning and assessment of progress towards Millennium Development Goal 5 (MDG 5), the target for which is a 75% reduction in the maternal mortality ratio (MMR) from 1990 to 2015. The authors assessed levels and trends in maternal mortality for 181 countries. They constructed a database of 2651 observations of maternal mortality for 181 countries for 1980-2008, from vital registration data, censuses, surveys, and verbal autopsy studies. They used robust analytical methods to generate estimates of maternal deaths and the maternal mortality ratio for each year between 1980 and 2008. They explored the sensitivity of their data to model specification and show the out-of-sample predictive validity of their methods. They estimated that there were 342 900 (uncertainty interval 302 100-394 300) maternal deaths worldwide in 2008, down from 526 300 (446 400-629 600) in 1980. The global maternal mortality ratio decreased from 422 (358-505) in 1980 to 320 (272-388) in 1990, and was 251 (221-289) per 100 000 live births in 2008. The yearly rate of decline of the global maternal mortality ratio since 1990 was 1.3% (1.0-1.5). During 1990-2008, rates of yearly decline in the maternal mortality ratio varied between countries, from 8.8% (8.7-14.1) in the Maldives to an increase of 5.5% (5.2-5.6) in Zimbabwe. More than 50% of all maternal deaths were in only six countries in 2008 (India, Nigeria, Pakistan, Afghanistan, Ethiopia, and the Democratic Republic of the Congo). In the absence of HIV, there would have been 281 500 (243 900-327 900) maternal deaths worldwide in 2008. Substantial, albeit varied, progress has been made towards MDG 5. Although only 23 countries are on track to achieve a 75% decrease in maternal mortality ratio by 2015, countries such as Egypt, China, Ecuador, and Bolivia have been achieving accelerated progress.

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http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)60518-1/fulltext

Editors’ Note: Both early maternal mortality defined as the death of women during pregnancy, childbirth, or in the 42 days after delivery, and late maternal mortality in the period from 43 days to 1 year post-delivery are notoriously difficult to measure accurately. This study drew on every available data source, tried to correct for misclassification, and ran predictive validity tests on their modelling approach. Late maternal mortality and mortality due to Incidental causes such as motor vehicle accidents, drowning, etc. are not included in the calculation of the maternal mortality ratio (MMR). Thus the MMR includes early maternal deaths due to direct obstetric causes, indirect causes (aggravated by pregnancy), and HIV infection causes, and is calculated as the number of maternal deaths per 100,000 live births. The target for Millennium Development Goal (MDG) 5 is a 75% reduction in the MMR between 1990 and 2015 which would require a 5.5% annual decline in the MMR when it has fallen 1.8% per year from 1980 to 2008. We need to speed up the decline to get on target. This stocktaking analysis has striking findings. Analysis of the 1.5% annual rate of decline in the number of maternal deaths from 1980 to 2008 reveals a disturbing trend. The decline was 1.8% annually between 1980 and 1990, dropping to 1.4% from 1990 to 2008. In fact, had there been no HIV epidemic, the decline overall would have been 2.2% per year, not 1.5%. With the proportion of global maternal deaths occurring in sub-Saharan Africa having increased from 23% in 1990 to 52% in 2008, as the HIV epidemic in the region deepened, it is clear that initiating antiretroviral therapy for pregnant women with HIV infection worldwide, but particularly in sub-Saharan Africa, could help get us on track. At the same time, we need to continue to address factors that influence maternal mortality and HIV such as education for girls - it rose from 1.5 years in 1980 to 4.4 years in 2008 in sub-Saharan Africa. Continued reductions in the total fertility rate, which fell from 3.7 in 1980 to 2.6 in 2008, acceleration in the slow increases in the coverage of skilled birth attendance, and specific tracking of HIV-related maternal mortality are top priorities. Preventing HIV infection in women, preventing unintended pregnancy in women who have HIV infection, and putting pregnant women with HIV infection on antiretroviral therapy for their own health would have rapid and sustained effects on maternal mortality in high HIV prevalence settings.

impact of joint epidemics of HIV and noncommunicable diseases

Millennium Development Goals

Drivers of inequality in millennium development goal progress statistical analysis.

Many low- and middle-income countries are not on track to reach the public health targets set out in the Millennium Development Goals (MDGs). The authors evaluated whether differential progress towards health MDGs was associated with economic development, public health funding (both overall and as percentage of available domestic funds), or health system infrastructure. They also examined the impact of joint epidemics of HIV and noncommunicable diseases, which may limit the ability of households to address child mortality and increase risks of infectious diseases. Stuckler and colleagues calculated each country's distance from its MDG goals for HIV, tuberculosis, and infant and child mortality targets for the year 2005 using the United Nations MDG database for 227 countries from 1990 to the present. They studied the association of economic development (gross domestic product [GDP] per capita in purchasing-power-parity), the relative priority placed on health (health spending as a percentage of GDP), real health spending (health system expenditures in purchasing-power-parity), HIV burden (prevalence rates among ages 15-49 y), and noncommunicable disease burden (age-standardised chronic disease mortality rates), with measures of distance from attainment of health MDGs. To avoid spurious correlations that may exist simply because countries with high disease burdens would be expected to have low MDG progress, and to adjust for potential confounding arising from differences in countries' initial disease burdens, they analysed the variations in rates of change in MDG progress versus expected rates for each country. While economic development, health priority, health spending, and health infrastructure did not explain more than one-fifth of the differences in progress to health MDGs among countries, burdens of HIV and noncommunicable diseases explained more than half of between-country inequalities in child mortality progress (R(2)-infant mortality = 0.57, R(2)-under 5 mortality = 0.54). HIV and noncommunicable disease burdens were also the strongest correlates of unequal progress towards tuberculosis goals (R(2) = 0.57), with noncommunicable diseases having an effect independent of HIV, consistent with micro-level studies of the influence of tobacco and diabetes on tuberculosis risks. Even after correcting for health system variables, initial child mortality, and tuberculosis diseases, the authors found that lower burdens of HIV and noncommunicable diseases were associated with much greater progress towards attainment of child mortality and tuberculosis MDGs than were gains in GDP. An estimated 1% lower HIV prevalence or 10% lower mortality rate from noncommunicable diseases would have a similar impact on progress towards the tuberculosis MDG as an 80% or greater rise in GDP, corresponding to at least a decade of economic growth in low-income countries. Unequal progress in health MDGs in low-income countries appears significantly related to burdens of HIV and noncommunicable diseases in a population, after correcting for potentially confounding socioeconomic, disease burden, political, and health system variables. The common separation between noncommunicable diseases, child mortality, and infectious syndromes among development programs may obscure interrelationships of illness affecting those living in poor households--whether economic (e.g., as money spent on tobacco is lost from child health expenditures) or biological (e.g., as diabetes or HIV enhance the risk of tuberculosis).

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http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000241
Editors’ Note: This thought-provoking article is essential reading for everyone focused on the 8 Millennium Development Goals (MDG), their 21 quantifiable targets, and 60 indicators of progress. It is a first attempt to analyse the determinants of global inequalities in progress toward the health MDGs 4 and 6. The 2015 targets and indicators for the 3 health MDGs are summarised in a box that would be handy on the wall above your desk. Unmet MDG progress in infant, child, and tuberculosis (TB) mortality, as well as HIV prevalence, suggests that fewer than half of low-income countries will achieve the 2015 targets for MDGs 4 and 6. This intriguing analysis of 227 countries found that likely explanatory suspects such as economic development (gross domestic product [GDP]), health spending as a per cent of GDP, and numbers of physicians per capita together explained only one-fifth of the differences in progress on these health MDGs between countries. What is making the difference? Burdens of HIV and non-communicable diseases (NCD) explained more than half of differences in infant mortality progress and were strongly associated with unequal progress on TB. A 1% drop in HIV prevalence or a 10% decline in mortality from non-communicable diseases such as heart disease, diabetes, cancer, tobacco-related lung disease, disabling mental disease, and accidents, would improve a country’s progress on TB as much as if its GDP rose by an unlikely 80%. For child mortality, the magnitude of effect was similar to a 40% rise in GDP. We know the strong links between HIV and TB, HIV and infant mortality, and HIV and under-five child mortality. However, we have underestimated the effects in low-income countries of co-existing epidemics of obesity due to the ‘nutrition transition’, lung disease due to aggressive marketing of tobacco products, and decreased physical activity due to urbanization on achievement of the health MDGs. Since the poorest households often face the greatest burden of non-communicable diseases and HIV, as well as being the most affected by child mortality and TB, we need to investigate these interrelationships and address them explicitly to get on track for 2015.

Increased risk of HIV-infection among school-attending orphans in rural Zimbabwe.

Orphans and HIV

Increased risk of HIV-infection among school-attending orphans in rural Zimbabwe.

In Zimbabwe around 1.1 million children have been orphaned due to AIDS. The authors conducted a survey among school-attending youth in rural south-eastern Zimbabwe in 2003, and examined the association between orphaning and risk of HIV. They enrolled 30 communities in three provinces. All students attending Year 2 of secondary school were eligible. Each completed a questionnaire and provided a finger-prick blood specimen for testing for HIV-1 and HSV-2 antibodies. Female participants were tested for pregnancy. Six thousand seven hundred and ninety-one participants were recruited (87% of eligible); 35% had lost one or both parents (20% of participants had lost their father; 6% their mother; and 9% both parents). Orphans were not poorer than non-orphans based on reported access to income, household structure and ownership of assets. There was strong evidence that orphans, and particularly those who had lost both parents, were at increased sexual risk, being more likely to have experienced early sexual debut; to have been forced to have sex; and less likely to have used condoms. Fifty-one students were HIV positive (0.75%). Orphans were three times more likely to be HIV infected than non-orphans (adjusted odds ratio = 3.4; 95% confidence interval: 1.8-6.6). Over 60% of those HIV positive were orphaned. Among school-going youth, the rates of orphaning were very high; there was a strong association between orphaning and increased risk of HIV, and evidence of greater sexual risk taking among orphans. It is essential that we understand the mechanisms by which orphaned children are at increased risk of HIV in order to target prevention and support appropriately.


Editors’ note: The Zimbabwe Demographic Health Survey of 2005-2006 estimated that 36% of children aged 15-17 years were orphaned, with rural young people in this age group more likely to be orphans than urban youth. This study of 6791 school-going adolescents found 35% had lost one or both parents. Although HIV prevalence was below 1%, almost two-thirds of those identified as HIV-positive were orphans. Male orphans were at almost three times greater risk of being infected and female orphans at more than four times greater risk of HIV infection than their non-orphan counterparts. Some of these orphans may have been infected vertically at birth or through breastfeeding but this is unlikely as half had lost only their fathers, the chance of surviving to age 15 in the absence of treatment is low, and there was increased reporting of sexual risk taking by orphans. Although the safety net of the extended family continues to shelter increasing numbers of orphans, programmes to reduce HIV-related risks among these young people are needed now and will be increasingly important as the epidemic continues to deepen.

immunologic response and HIV

Measures of site resourcing predict virologic suppression, immunologic response and HIV disease progression following highly active antiretroviral therapy (HAART) in the TREAT Asia HIV Observational Database (TAHOD).

Surrogate markers of HIV disease progression are HIV RNA in plasma viral load and CD4 cell count (immune function). Despite improved international access to antiretrovirals, surrogate marker diagnostics are not routinely available in resource-limited settings. Therefore, the objective was to assess effects of economic and diagnostic resourcing on patient treatment outcomes. Analyses were based on 2333 patients initiating antiretroviral therapy from 2000 onwards. Sites were categorized by World Bank country income criteria (high/low) and annual frequency of plasma viral load (>/=3, 1-2 or <1)>/=3 or <3)>Increased disease progression was associated with site-reported plasma viral load testing less than once per year [hazard ratio (HR)=1.4; P=0.032], severely symptomatic HIV infection (HR=1.4; P=0.003) and hepatitis C virus coinfection (HR=1.8; P=0.011). A total of 1120 patients (48.2%) had change in CD4 cell count data. Smaller increases were associated with older age (P<0.001) p="0.043)." or="0.28;">35% increase in disease progression in patients from sites with plasma viral load testing less than once per year.


Editor’s note: Setting out to determine the extent to which clinical resourcing affected patient outcomes in 17 clinical sites in Asia, this observational study followed 2333 patients. An increased risk of disease progression was found for patients at sites reporting that viral load testing was performed less than once a year, with a 35% increased risk of developing AIDS or dying. Rather than using viral load testing to monitor treatment efficacy, it is possible that, in the face of resource constraints, clinics were using viral load testing to confirm treatment failure. Lack of viral load testing increases the likelihood that patients will be maintained on failing regimens and develop highly resistant HIV. Expanding access to viral load testing and developing cheaper viral load tests that can be used more frequently to monitor treatment outcomes is an urgent global priority as access to antiretroviral therapy continues to expand.

according to the HIV type in the IeDEA West Africa collaboration.

First-year lymphocyte T CD4+ response to antiretroviral therapy according to the HIV type in the IeDEA West Africa collaboration.

The objective of the study was to compare the lymphocyte T CD4+ (CD4) response to combinations of antiretroviral therapy in HIV-1, HIV-2 and dually positive patients in West Africa. The study was a collaboration of 12 prospective cohorts of HIV-infected adults followed in Senegal (2), Gambia (1), Mali (2), Benin (1) and Côte d'Ivoire (6). Nine thousand, four hundred and eighty-two patients infected by HIV-1 only, 270 by HIV-2 only and 321 dually positive, who initiated an antiretroviral therapy. CD4 change over a 12-month period. Observed CD4 cell counts at treatment initiation were similar in the three groups [overall median 155, interquartile range (IQR) 68; 249 cells/microl). In HIV-1 patients, the most common antiretroviral therapy regimen was two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor (N = 7714) as well as for dually positive patients (N = 135). HIV-2 patients were most often treated with a protease inhibitor-based regimen (N = 193) but 45 of them were treated with an non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy. In those treated with a non-nucleoside reverse transcriptase inhibitor-containing regimen, the estimated mean CD4 change between 3 and 12 months was significantly lower in HIV-2 (-41 cells/microl per year) and dually positive patients (+12 cells/microl per year) compared to HIV-1 patients (+69 cells/microl per year, overall P value 0.01). The response in HIV-2 and dually positive patients treated by another regimen (triple nucleoside reverse transcriptase or protease inhibitor-containing antiretroviral therapy) was not significantly different than the response obtained in HIV-1-only patients (all P values >0.30). An optimal CD4 response to antiretroviral therapy in West Africa requires determining HIV type prior to initiation of antiretroviral drugs. Non-nucleoside reverse transcriptase inhibitors are the mainstay of first-line antiretroviral therapy in West Africa but are not adapted to the treatment of HIV-2 and dually positive patients.


Editor’s note: Non-nucleoside reverse transcriptase inhibitors (NNRTI) are part of first-line regimens in West Africa, the epicenter of the HIV-2 epidemic, but are inappropriate for treatment of HIV-2 infection. Although HIV-2 infection has a longer symptom-free period, lower viral load, and slower disease progression, it can lead to AIDS. This observational study of more than 9000 patients in West Africa found poor CD4+ responses to treatment in patients with HIV-2 infection placed on NNRTI but comparable responses to treatment in people with HIV-2 infection, dual infections, and HIV-1 infection placed on protease inhibitor-containing regimens. This points to the need for medical training, appropriate medications, and diagnostic protocols at clinic level but also underscores the rationale for randomized controlled trials to determine the best drug regimens for patients with HIV-2 infection.

Human Rights

Human Rights

Access to pain treatment as a human right.

Almost five decades ago, governments around the world adopted the 1961 Single Convention on Narcotic Drugs which, in addition to addressing the control of illicit narcotics, obligated countries to work towards universal access to the narcotic drugs necessary to alleviate pain and suffering. Yet, despite the existence of inexpensive and effective pain relief medicines, tens of millions of people around the world continue to suffer from moderate to severe pain each year without treatment. Significant barriers to effective pain treatment include: the failure of many governments to put in place functioning drug supply systems; the failure to enact policies on pain treatment and palliative care; poor training of healthcare workers; the existence of unnecessarily restrictive drug control regulations and practices; fear among healthcare workers of legal sanctions for legitimate medical practice; and the inflated cost of pain treatment. These barriers can be understood not only as a failure to provide essential medicines and relieve suffering but also as human rights abuses. According to international human rights law, countries have to provide pain treatment medications as part of their core obligations under the right to health; failure to take reasonable steps to ensure that people who suffer pain have access to adequate pain treatment may result in the violation of the obligation to protect against cruel, inhuman and degrading treatment.

Editors’ note: Low- and middle-income countries are home to half of all cancer patients and more than 90% of HIV infections, yet they consume only 6% of the morphine used worldwide. Although the International Narcotics Control Board, which monitors the implementation of the UN drug conventions, drew attention in 1995 to the dual drug control obligation to ensure adequate availability of narcotic drugs, including opiates, for medical and scientific purposes, while preventing illicit production, trafficking, and use of such drugs, an estimated 80% of the world’s population has either no access or insufficient access to treatment for moderate to severe pain. Chronic pain, a common symptom of both cancer and HIV disease, has a profound impact on the quality of life, reduces treatment adherence, and influences the course of disease – it is one of the most significant causes of suffering and disability worldwide. Overcoming a vicious cycle of under-treatment requires governments to develop pain management and palliative care policies, reform regulations that impede access, institute health care worker training, and ensure affordability, including through investigating the feasibility of local manufacture.

Restricted genetic diversity of HIV-1 subtype

Prevention of Mother-To- Child Transmission

Restricted genetic diversity of HIV-1 subtype C envelope glycoprotein from perinatally infected

Mother-to-child transmission of HIV-1 remains a significant problem in the resource-constrained settings where anti-retroviral therapy is still not widely available. Understanding the earliest events during HIV-1 transmission and characterizing the newly transmitted or founder virus is central to intervention efforts. In this study, the authors analyzed the viral env quasispecies of six mother-infant transmission pairs and characterized the genetic features of envelope glycoprotein that could influence HIV-1 subtype C perinatal transmission. The V1-V5 region of env was amplified from 6 mother-infant transmission pairs baseline samples and 334 DNA sequences in total were analyzed. A comparison of the viral population derived from the mother and infant revealed a severe genetic bottleneck occurring during perinatal transmission, which was characterized by low sequence diversity in the infant. Phylogenetic analysis indicates that most likely in all their infant subjects a single founder virus was responsible for establishing infection. Furthermore, the newly transmitted viruses from the infant had significantly fewer potential N-linked glycosylation sites in Env V1-V5 region and showed a propensity to encode shorter variable loops compared to the nontransmitted viruses. In addition, a similar intensity of selection was seen between mothers and infants with a higher rate of synonymous (dS) compared to nonsynonymous (dN) substitutions evident (dN/dS<1).>strong genetic bottleneck occurs during perinatal transmission of HIV-1 subtype C. This is evident through population diversity and phylogenetic patterns where a single viral variant appears to be responsible for infection in the infants. As a result the newly transmitted viruses are less diverse and harbored significantly less glycosylated envelope. This suggests that viruses with the restricted glycosylation in envelope glycoprotein appeared to be preferentially transmitted during HIV-1 subtype C perinatal transmission. In addition, their findings also indicated that purifying selection appears to predominate in shaping the early intrahost evolution of HIV-1 subtype C envelope sequences.

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Editor’s note: All six infants in this study were negative for HIV at birth by PCR (polymerase chain reaction) and viral isolation, suggesting that transmission occurred during delivery or breastfeeding. They all had passively acquired maternal antibody, which may have imposed a selection pressure on the transmitted virus. The low amount of maternal virus they were exposed to through breastfeeding may also have contributed to the genetic bottleneck documented here. Although the mothers had a variety of viral quasispecies, only a single founder virus was transmitted. However, that virus had low sequence diversity, restricted glycosylation in the Env V1-V5 region, and a higher replicative fitness suggesting that it was better able to establish efficient replication in its new host. Four of these infants were fast progressors, dying before the age of 1 year. Studies such as this one characterising newly transmitted or founder viruses can help inform new interventions to prevent mother-to-child transmission.

Thursday, September 27, 2012

Child Transmission of HIV in Johannesburg, South Africa.

Prevention of Mother-To- Child Transmission

Effects of Highly Active Antiretroviral Therapy Duration and Regimen on Risk for Mother-to-Child Transmission of HIV in Johannesburg, South Africa.

Limited information exists about effects of different antiretroviral therapy regimens and duration of regimens on mother-to-child transmission of HIV among women in Africa who start treatment for advanced immunosuppression. Between January 2004 to August 2008, 1142 women were followed at antenatal antiretroviral clinics in Johannesburg. Predictors of mother-to-child transmission (positive infant HIV DNA polymerase chain reaction at 4-6 weeks) were assessed with multivariate logistic regression. Mean age was 30.2 years (SD = 5.0) and median baseline CD4 count was 161 cells per cubic millimeter (SD = 84.3). Antiretroviral therapy duration at time of delivery was a mean 10.7 weeks (SD = 7.4) for the 85% of women who initiated treatment during pregnancy and 93.4 weeks (SD = 37.7) for those who became pregnant on antiretroviral therapy. Overall mother-to-child transmission rate was 4.9% (43 of 874), with no differences detected between antiretroviral therapy regimens. Mother-to-child transmission rates were lower in women who became pregnant on antiretroviral therapy than those initiating antiretroviral therapy during pregnancy (0.7% versus 5.7%; P = 0.01). In the latter group, each additional week of treatment reduced odds of transmission by 8% (95% confidence interval: 0.87 to 0.99, P = 0.02). Late initiation of antiretroviral therapy is associated with increased risk of mother-to-child transmission. Strategies are needed to facilitate earlier identification of HIV-infected women.

For abstract access click here:
Editors’ note: Viral suppression typically occurs after 10-16 weeks of antiretroviral therapy and this likely explains the strong association found in this study between duration of antiretroviral treatment and HIV transmission to infants, with each additional week of treatment reducing the risk of HIV transmission. Thus it is no surprise that women who were on antiretroviral treatment when they became pregnant were significantly less likely to transmit HIV to their infants than women who were identified as treatment-eligible during pregnancy. In fact, there were no transmissions among women who were on antiretroviral treatment for more than 32 weeks before delivery. What is surprising is that pregnancy was planned in only 28.6% of women who became pregnant on treatment and 31.4% of those who started treatment during pregnancy. Since all of these women knew their HIV status, better integration of family planning services with HIV services could help avoid unplanned pregnancy and reduce infant infections even further.

Association of schistosomiasis with false positive HIV test

Association of schistosomiasis with false positive HIV test results in an African adolescent population.

The aim of the study was to investigate factors associated with the high rate of false positive test results observed on the 4(th) generation Murex HIV Ag/Ab Combination EIA when used in Tanzania. Clinical and socio-demographic factors associated with false positive HIV results were analysed in 6940 Tanzanian adolescents and young adults in the Northwestern region. Immunological factors, including IgG antibodies to malaria and schistosomiasis, heterophile antibody and rheumatoid factor titre, were analysed in a sub-sample of 284 Murex negative and 240 false positive sera. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals (CI). HIV false positive test results were associated with evidence of other infections. False positivity was strongly associated with increasing levels of Schistosoma haematobium worm IgG1, with adolescents with ODs in the top quartile at highest risk (adjusted OR=40.7, CI=8.5-194.2 compared with those in the bottom quartile). False positivity was also significantly associated with increasing S. mansoni egg IgG1, and RF titre >/= 80 (adjusted OR=8.2, CI=2.8-24.3). There was a significant negative association between Murex false positivity and levels of S. mansoni worm IgG1 and IgG2, and Plasmodium falciparum IgG1 and IgG4. In Africa, endemic infections may affect the specificity of immunoassays for HIV infection. Caution should be used when interpreting 4(th) generation HIV test results in African adolescent populations.

Editor’s note: Cross-reactivity between HIV-1 peptides and antibodies to Schistosoma appear to have contributed to the very high false positive HIV test results found among adolescents in this Tanzanian study. Pressure to develop highly sensitive HIV assays so that early infections are not missed has led to development of 4th generation assays that detect both HIV antigen and HIV antibody. Such tests clearly don’t perform well in adolescents that are disproportionately affected by schistosomiasis. In this study, schistosomiasis IgG antibody was associated with Rheumatoid factor (RF) titres and these in turn were associated with false positive HIV test results. RF is found in autoimmune diseases such as rheumatoid arthritis but it is also associated with viral, bacterial, and other parasitic infections. Further research on the cross-reactivity of HIV diagnostic tests is warranted, with the findings used in the design and evaluation of tests specific for African populations.

Co-Morbidity: HIV and Worms

Co-Morbidity: HIV and Worms

Association of schistosomiasis with false positive HIV test results in an African adolescent population.

The aim of the study was to investigate factors associated with the high rate of false positive test results observed on the 4(th) generation Murex HIV Ag/Ab Combination EIA when used in Tanzania. Clinical and socio-demographic factors associated with false positive HIV results were analysed in 6940 Tanzanian adolescents and young adults in the Northwestern region. Immunological factors, including IgG antibodies to malaria and schistosomiasis, heterophile antibody and rheumatoid factor titre, were analysed in a sub-sample of 284 Murex negative and 240 false positive sera. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals (CI). HIV false positive test results were associated with evidence of other infections. False positivity was strongly associated with increasing levels of Schistosoma haematobium worm IgG1, with adolescents with ODs in the top quartile at highest risk (adjusted OR=40.7, CI=8.5-194.2 compared with those in the bottom quartile). False positivity was also significantly associated with increasing S. mansoni egg IgG1, and RF titre >/= 80 (adjusted OR=8.2, CI=2.8-24.3). There was a significant negative association between Murex false positivity and levels of S. mansoni worm IgG1 and IgG2, and Plasmodium falciparum IgG1 and IgG4. In Africa, endemic infections may affect the specificity of immunoassays for HIV infection. Caution should be used when interpreting 4(th) generation HIV test results in African adolescent populations.

For abstract access click here:
Editor’s note: Cross-reactivity between HIV-1 peptides and antibodies to Schistosoma appear to have contributed to the very high false positive HIV test results found among adolescents in this Tanzanian study. Pressure to develop highly sensitive HIV assays so that early infections are not missed has led to development of 4th generation assays that detect both HIV antigen and HIV antibody. Such tests clearly don’t perform well in adolescents that are disproportionately affected by schistosomiasis. In this study, schistosomiasis IgG antibody was associated with Rheumatoid factor (RF) titres and these in turn were associated with false positive HIV test results. RF is found in autoimmune diseases such as rheumatoid arthritis but it is also associated with viral, bacterial, and other parasitic infections. Further research on the cross-reactivity of HIV diagnostic tests is warranted, with the findings used in the design and evaluation of tests specific for African populations.

HIV prevention, treatment, and care services for people

HIV prevention, treatment, and care services for people who inject drugs: a systematic review of global, regional, and national coverage.

Previous reviews have examined the existence of HIV prevention, treatment, and care services for persons who inject drugs worldwide, but they did not quantify the scale of coverage. Mathers and colleagues undertook a systematic review to estimate national, regional, and global coverage of HIV services in people who inject drugs. The authors did a systematic search of peer-reviewed (Medline, BioMed Central), internet, and grey-literature databases for data published in 2004 or later. A multistage process of data requests and verification was undertaken, involving UN agencies and national experts. National data were obtained for the extent of provision of the following core interventions for persons who inject drugs: needle and syringe programmes, opioid substitution therapy and other drug treatment, HIV testing and counselling, antiretroviral therapy, and condom programmes. They calculated national, regional, and global coverage of needle and syringe programmes, opioid substitution therapy, and antiretroviral therapy on the basis of available estimates of persons who inject drugs population sizes. By 2009, needle and syringe programmes had been implemented in 82 countries and opioid substitution therapy in 70 countries; both interventions were available in 66 countries. Regional and national coverage varied substantially. Australasia (202 needle-syringes per individuals who inject drugs per year) had by far the greatest rate of needle-syringe distribution; Latin America and the Caribbean (0.3 needle-syringes per individuals who inject drugs per year), Middle East and north Africa (0.5 needle-syringes per individuals who inject drugs per year), and sub-Saharan Africa (0.1 needle-syringes per individuals who inject drugs per year) had the lowest rates. Opioid substitution therapy coverage varied from less than or equal to one recipient per 100 persons who inject drugs in central Asia, Latin America, and sub-Saharan Africa, to very high levels in western Europe (61 recipients per 100 individuals who inject drugs). The number of persons who inject drugs receiving antiretroviral therapy varied from less than one per 100 HIV-positive persons who inject drugs (Chile, Kenya, Pakistan, Russia, and Uzbekistan) to more than 100 per 100 HIV-positive persons who inject drugs in six European countries. Worldwide, an estimated two needle-syringes (range 1-4) were distributed per persons who inject drugs per month, there were eight recipients (6-12) of opioid substitution therapy per 100 persons who inject drugs, and four persons who inject drugs (range 2-18) received antiretroviral therapy per 100 HIV-positive persons who inject drugs. Worldwide coverage of HIV prevention, treatment, and care services in persons who inject drugs populations is very low. There is an urgent need to improve coverage of these services in this population at higher risk from HIV.

Although the number of countries with core HIV prevention services (needle-syringe programmes [NSP], opioid substitution therapy [OST], and antiretroviral therapy[ART]) for people who inject drugs is growing, coverage is highly variable and it remains very poor in the majority of countries. Outside of sub-Saharan Africa, one-third of all HIV infections are acquired through injecting with contaminated equipment. Unless there is concerted action to address the risk environments that decrease the likelihood that sterile injecting equipment can be used, HIV transmission through injecting will continue to flourish. Rapid expansion of coverage for the 9 core interventions identified as essential by UNODC, WHO, and UNAIDS is urgently needed. In addition to NSP, OST, and ART, these are voluntary counselling and testing; prevention and treatment of sexually transmitted infections; condom programming for injecting drug users and partners; tailored information, education and communication; vaccination, diagnosis, and treatment of viral hepatitis; and prevention, diagnosis, and treatment of tuberculosis. New interventions are not needed, rather policies to increase implementation of proven HIV programmes clearly are – and that will require that policy-makers recognise that it is high time for rights-based, evidence-informed policies and programming.

confer enhanced immune coverage of diverse HIV strains in monkeys.

Mosaic vaccines elicit CD8(+) T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys.

An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8(+) T lymphocytes that control HIV replication and CD4(+) T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates. Here Santra and colleagues immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8(+) T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8(+) T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant

In this macaque study, a mosaic immunogen was created by combining the gag and nef genes from geographically and sub-type diverse natural strains of HIV. A much broader immune response was elicited in macaques with this recombinant mix than with a consensus protein. Cellular immune responses to mosaic immunogens recognized a greater diversity of viral epitope variants, with CD+8 T lymphocytes showing significantly greater cross-reactivity, not only to more epitopes but also to more variant sequences of specific epitopes. Keeping up with viral evolution means expanding the breadth and depth of our CD8+ cytotoxic T lymphocyte responses – it looks like mosaic vaccines may be able to give us the leg up that we

site from long-term survivors of HIV infection.

Neutralization of genetically diverse HIV-1 strains by IgA antibodies to the gp120-CD4-binding site from long-term survivors of HIV infection.

The aim of the study was to identify an HIV epitope suitable for vaccine development. Diverse HIV-1 strains express few structurally constant regions on their surface vulnerable to neutralizing antibodies. The mostly conserved CD4-binding site of gp120 is essential for host cell binding and infection by the virus. Antibodies that recognize the CD4-binding site are rare, and one component of the CD4-binding site, the 421-433 peptide region, expresses B-cell superantigenic character, a property predicted to impair the anti-CD4-binding site adaptive immune response. IgA samples purified from the plasma of patients with HIV infection were analyzed for the ability to bind synthetic mimetics containing the 416-433 gp120 region and full-length gp120. Infection of peripheral blood mononuclear cells by clinical HIV isolates was measured by p24 ELISA. IgA preparations from three patients with subtype B infection for 19-21 years neutralized heterologous, coreceptor CCR5-dependent subtype A, B, C, D, and AE strains with exceptional potency. The IgAs displayed specific binding of a synthetic 416-433 peptide mimetic dependent on recognition of the CD4-binding residues located in this region. Immunoadsorption, affinity chromatography, and mutation procedures indicated that HIV neutralization occurred by IgA recognition of the CD4-binding site. These observations identify the 421-433 peptide region as a vulnerable HIV site to which survivors of infection can produce powerful neutralizing antibodies. This indicates that the human immune system can bypass restrictions on the adaptive B cell response to the CD4-binding site, opening the route to targeting the 421-433 region for attaining control of HIV infection.

Studying the immune response of 3 long-term survivors, who had contracted HIV as children from contaminated blood products 19-21 years previously, revealed a region of HIV that is structurally conserved in genetically diverse HIV strains around the world and is immunogenic, meaning that it stimulates a robust immune response. Purified plasma IgA preparations from each of these 3 patients who were infected with sub-type B neutralized 18 genetically diverse clinical isolates from subtypes A, B, C, D, and AE. This is exciting news because the search for such a conserved epitope, i.e. the part of the virus that is recognized by the immune system and to which an antibody binds, is a holy grail. The site is the 421-433 region of the CD4 binding site of the virus. Interestingly, the autoimmune disease systemic lupus erythematosus produces antibodies to this epitope - and HIV and lupus rarely co-exist.

Wednesday, September 26, 2012

government size, HIV prevalence, debt relief

Government spending on health from domestic sources is an important indicator of a government's commitment to the health of its people, and is essential for the sustainability of health programmes. The study aimed to systematically analyse all data sources available for government spending on health in developing countries; describe trends in public financing of health; and test the extent to which they were related to changes in gross domestic product (GDP), government size, HIV prevalence, debt relief, and development assistance for health to governmental and non-governmental sectors. The authors did a systematic analysis of all data sources available for government expenditures on health as agent (GHE-A) in developing countries, including government reports and databases from WHO and the International Monetary Fund (IMF). GHE-A consists of domestically and externally financed public health expenditures. They assessed the quality of these sources and used multiple imputation to generate a complete sequence of GHE-A. With these data and those for development assistance for health to governments, the authors estimated government spending on health from domestic sources. They used panel-regression methods to estimate the association between government domestic spending on health and GDP, government size, HIV prevalence, debt relief, and development assistance for health disbursed to governmental and non-governmental sectors. The authors tested the robustness of our conclusions using various models and subsets of countries. In all developing countries, public financing of health in constant US$ from domestic sources increased by nearly 100% (IMF 120%; WHO 88%) from 1995 to 2006. Overall, this increase was the product of rising GDP, slight decreases in the share of GDP spent by government, and increases in the share of government spending on health. At the country level, while shares of government expenditures to health increased in many regions, they decreased in many sub-Saharan African countries. The statistical analysis showed that development assistance for health to government had a negative and significant effect on domestic government spending on health such that for every US$1 of development assistance for health to government, government health expenditures from domestic resources were reduced by $0.43 (p=0) to $1.14 (p=0). However, development assistance for health to the non-governmental sector had a positive and significant effect on domestic government health spending. Both results were robust to multiple specifications and subset analyses. Other factors, such as debt relief, had no detectable effect on domestic government health spending. To address the negative effect of development assistance for health on domestic government health spending, Lu and colleagues recommend strong standardised monitoring of government health expenditures and government spending in other health-related sectors; establishment of collaborative targets to maintain or increase the share of government expenditures going to health; investment in the capacity of developing countries to effectively receive and use development assistance for health; careful assessment of the risks and benefits of expanded development assistance for health to non-governmental sectors; and investigation of the use of global price subsidies or product transfers as mechanisms for development assistance for health.

‘Fungibility’ of foreign aid occurs when aid substitutes for government spending, resulting in ‘sub-additionality’ rather ‘additionality’, the goal of most development assistance. Among the factors that are complicating discussions of its extent, and what to do about it, are incomplete estimates of development assistance for health (DAH) in the first place (‘untraceable DAH’), variations in accounting practices at country level for total health expenditures, and lack of information about what the resources taken from ministries of health actually are spent on. Although African leaders pledged in 2001 in Abuja to devote 15% or more of their yearly budgets to the health sector and absolute amounts of domestic funding being spent on health have increased 132-242% between 1995 and 2006 in low-income countries in sub-Saharan Africa, the largest reductions in the proportion that domestic funding contributes to health spending occurred in countries with the largest HIV epidemics and the largest DAH contributions. It is not surprising that increasing domestic contributions are overshadowed by external support as countries try to turn around HIV epidemics that are sapping development. Although investment in effective public expenditure management systems is clearly needed to improve accountability from the global level right through to local level, it is important to remember that country ownership starts with nationally set priorities and reallocation of funding to match these.

the importance of network structures in the epidemiology of HIV


The extent and structure of sexual networks have important consequences for the spread of sexually transmitted diseases such as HIV. However, very few datasets currently exist that allow a detailed investigation of sexual networks in sub-Saharan African settings where HIV epidemics have become generalized. In this paper, the authors describe the context and methods of the Likoma Network Study, one of the few studies that have collected extensive information on sexual networks in sub-Saharan Africa. They start by reviewing theoretical arguments and empirical studies emphasizing the importance of network structures in the epidemiology of HIV and other sexually transmitted infections. The island setting of this study is described, and the authors argue that the choice of an island as a research site limited potential biases that may make the collection of sexual network data difficult. Helleringer and colleagues then document their empirical strategy for the collection of sexual network data and the subsequent identification of sexual network partners. A description of the protocol for the collection of biomarker data (HIV infection) is provided. Finally, they present initial results relating to the socioeconomic context of the island, the size and composition of sexual networks, the quality of the sexual network data, the determinants of successful contact tracing during the Likoma Network Study, and the prevalence of HIV in the study population.

Although Likoma Island in Lake Malawi is 18 square kilometres and has a population of only 7000 people living in a dozen villages, it has contributed substantially to our understanding of the role of sexual networks in generalized epidemics. Only 7 of 1235 households refused to be interviewed about socioeconomic information and in the seven villages chosen for the sexual network survey (representing 50.9% of 18-35 year olds on Likoma), the participation rate was 88%. Whereas Demographic and Heath Surveys are ‘egocentric’, meaning that they rely on self-reports that have to be taken at face value, the Likoma Study is ‘socio-centric’. It provides detailed data on the extent and structure of sexual networks and evaluates data quality by determining rates of inter-partner agreement about sexual relationships. Understanding patterns of connectivity and overlap between relationships informs modelling of the sexual spread of HIV and can assist in the design of context-appropriate HIV prevention programmes. A big challenge is to explain how individuals are part of sexual networks, even if they themselves have only one partner.

HIV mortality and infection in India

HIV mortality and infection in India: estimates from nationally representative mortality survey of 1.1 million homes.

Jha P, Kumar R, Khera A, Bhattacharya M, Arora P, Gajalakshmi V, Bhatia P, Kam D, Bassani DG, Sullivan A, Suraweera W, McLaughlin C, Dhingra N, Nagelkerke N; Million Death Study Collaborators. BMJ 2010;340:c62

The aim of the study was to determine the rates of death and infection from HIV in India by analysing a nationally representative survey of deaths. The study population covered 1.1 million homes in India. The population included 123,000 deaths at all ages from 2001 to 2003. The main outcomes were HIV mortality and infection. HIV accounted for 8.1% (99% confidence interval 5.0% to 11.2%) of all deaths among adults aged 25-34 years. In this age group, about 40% of deaths from HIV were due to AIDS, 26% were due to tuberculosis, and the rest were attributable to other causes. Nationally, HIV infection accounted for about 100,000 (59,000 to 140,000) deaths or 3.2% (1.9% to 4.6%) of all deaths among people aged 15-59 years. Deaths from HIV were concentrated in the states and districts with higher HIV prevalence and in men. The mortality results imply an HIV prevalence at age 15-49 years of 0.26% (0.13% to 0.39%) in 2004, comparable to results from a 2005/6 household survey that tested for HIV (0.28%). Collectively, these data suggest that India had about 1.4-1.6 million HIV infected adults aged 15-49 years in 2004-6, about 40% lower than the official estimate of 2.3 million for 2006. All cause mortality increased in men aged 25-34 years between 1997 and 2002 in the states with higher HIV prevalence but declined after that. HIV prevalence in young pregnant women, a proxy measure of incidence in the general population, fell between 2000 and 2007. Thus, HIV mortality and prevalence may have fallen further since this study. HIV attributable death and infection in India is substantial, although it is lower than previously estimated.

is important about this study is not the impressively large numbers – 900 field interviewers recorded symptoms, signs, and key circumstances leading to death for 132, 626 deaths that occurred in a nationally representative sample of 1.1 million homes. Rather, it is that setting up a sample registration system from a national census, as the Government of India has done, creates a framework for reporting causes of death through household visits. This information can be triangulated with data from cohort studies of people living with HIV, results of demographic and health surveys that include HIV testing, sentinel surveillance using HIV testing, and other data to improve national monitoring of HIV and measure the population-level impact of prevention and treatment services.