HIV This Week

Wawer MJ, Makumbi F, Kigozi G, Serwadda D, Watya S, Nalugoda F, Buwembo D, Ssempijja V, Kiwanuka N, Moulton LH, Sewankambo NK, Reynolds SJ, Quinn TC, Opendi P, Iga B, Ridzon R, Laeyendecker O, Gray RH. Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial. Lancet. 2009 Jul 18;374(9685):229-37.

Observational studies have reported an association between male circumcision and reduced risk of HIV infection in female partners. Wawer and colleagues set out to assess whether circumcision in HIV-infected men would reduce transmission of the virus to female sexual partners. 922 uncircumcised, HIV-infected, asymptomatic men aged 15-49 years with CD4-cell counts 350 cells per microL or more were enrolled in this unblinded, randomised controlled trial in Rakai District, Uganda. Men were randomly assigned by computer-generated randomisation sequence to receive immediate circumcision (intervention; n=474) or circumcision delayed for 24 months (control; n=448). HIV-uninfected female partners of the randomised men were concurrently enrolled (intervention, n=93; control, n=70) and followed up at 6, 12, and 24 months, to assess HIV acquisition by male treatment assignment (primary outcome). A modified intention-to-treat (ITT) analysis, which included all concurrently enrolled couples in which the female partner had at least one follow-up visit over 24 months, assessed female HIV acquisition by use of survival analysis and Cox proportional hazards modelling. This trial is registered with ClinicalTrials.gov, number NCT00124878. The trial was stopped early because of futility . 92 couples in the intervention group and 67 couples in the control group were included in the modified ITT analysis. 17 (18%) women in the intervention group and eight (12%) women in the control group acquired HIV during follow-up (p=0.36). Cumulative probabilities of female HIV infection at 24 months were 21.7% (95% CI 12.7-33.4) in the intervention group and 13.4% (6.7-25.8) in the control group (adjusted hazard ratio 1.49, 95% CI 0.62-3.57; p=0.368). Circumcision of HIV-infected men did not reduce HIV transmission to female partners over 24 months; longer-term effects could not be assessed. Condom use after male circumcision is essential for HIV prevention.

Editors’ note: When this trial was stopped for futility because it lacked the power to answer the question of whether or not HIV-positive men who get circumcised are less likely to transmit HIV, it became clear that we would likely never know the definitive answer to this question. However, a key insight gained from the trial is the importance of sexual abstinence until complete wound healing. Premature resumption of sex may delay wound healing, increase the risk that a man may acquire a new HIV infection, and increase the risk of HIV transmission to sexual partners. These researchers previously found that 93% of HIV-positive men circumcised at CD4 › 350 cells were healed by 6 weeks post-circumcision. However, in this trial, 22% of couples resumed sex early and 25% of the men had not disclosed their HIV status, underscoring the importance of joint couple counselling and testing to learn serostatus and plan abstinence strategies for the healing period.

Mehta et al set out to evaluate whether sexual intercourse soon after adult male circumcision affected HIV risk by conducting a combined analysis of data from African trials of men who were randomized to and underwent circumcision. The authors examined two associations: early sex (intercourse <42 days after circumcision) and HIV acquisition at 3 months for the Orange Farm and Kisumu trials and at 6 months for the Rakai and Kisumu trials and incomplete wound healing at 1 month and seroconversion at 3 and 6 months for the Kisumu trial and at 6 months for the Rakai trial. Early sex was reported by 3.9% of participants in Kisumu, 5.4% in Rakai, and 22.5% in Orange Farm. HIV seroprevalence was 0.0% at 3 months and 1.9% at 6 months among 18-24-year-olds reporting early sex and 0.2% at 3 months and 0.6% at 6 months among those who did not report early sex. In pooled analyses, men reporting early sex did not have higher HIV infection risk at 3 or 6 months. In Kisumu, 16 (1.3%) men had incomplete wound healing at the 30-day visit. One (6.3%) of these seroconverted at 3 months compared with 2 (0.2%) of 1246 men with complete wound healing (P = 0.075). No association was observed between incomplete wound healing and seroconversion for Rakai participants. The authors conclude that most men delayed intercourse after circumcision. Early sex after circumcision was not associated with HIV risk, although the study power was limited. Nevertheless, men should delay intercourse to limit the potential for increased HIV risk until complete wound healing.

Editors’ note: In an excellent move, these three trials pooled their data to assess the risk to HIV-negative men of early resumption of sex after circumcision. Slightly different definitions of wound healing (e.g. Rakai: healthy scar formation, no scab or open wound; Kisumu: no scab, open wound, swelling or redness), different follow-up periods, and the low number of seroconversions observed in the 6 months after circumcision limited the power to detect meaningful associations. In all 3 trials, early sex was reported more often among men who were married or living as married. For such men, involving women in decision-making about circumcision would facilitate couple counselling about avoiding sexual intercourse during the healing period and practising safer sex thereafter.

Des Jarlais DC, McKnight C, Goldblatt C, Purchase D. Doing harm reduction better: syringe exchange in the United States. Addiction. 2009 Feb 10. [Epub ahead of print]

To trace the growth of syringe exchange programs in the United States since 1994-95 and assess the current state of syringe exchange programs, annual surveys of US syringe exchange programs known to the North American Syringe Exchange Network (NASEN) were mailed to executive directors with follow-up interviews by telephone and/or e-mail. Response rates have varied between 70% and 88% since surveys were initiated in 1996. The numbers of programs known to NASEN have increased from 68 in 1994-95 to 186 in 2007. Among programs participating in the survey, numbers of syringes exchanged have increased from 8.0 million per year to 29.5 million per year, total annual budgets have increased from $6.3 to $19.6 million and public funding (from state and local governments) has increased from $3.9 to $14.4 million. In 2007, 89% of programs permitted secondary exchange and 76% encouraged it. Condoms, referrals to substance abuse treatment; human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV) counselling and testing and naloxone for overdose were among the most commonly provided services in addition to basic syringe exchange. Each of these services was provided by 40% or more of syringe exchange programs in 2007. While syringe exchange has remained controversial in the United States, there has been very substantial growth in numbers of programs, syringes exchange and program budgets. Utilizing secondary exchange to reach large numbers of injecting drug users and utilizing syringe exchange programs as a new platform for providing health and social services beyond basic syringe exchange have been the two major organizational strategies in the growth of syringe exchange programs in the United States.

Editors’ note: Two-thirds of these US programmes do not adhere to a restrictive ‘one-for-one’ needle exchange policy and 89% permit secondary exchange, allowing an individual participant to exchange for peers who do not necessarily attend the exchange. These policies have served to increase the numbers of sterile syringes available to injecting drug users with the result that HIV incidence in the USA has declined to under 1 per 100 person years and the majority of new infections among injecting drug users appear to be sexually transmitted. The recent Congress bill lifting the 20-year ban on federal funding for needle exchange http://www.speaker.gov/blog/?p=1885 may encourage more equitable service coverage across the US, reduce stigmatisation of drug users, and facilitate a move toward integration of services for drug users into the regular health system.

Price JE, Leslie JA, Welsh M, Binagwaho A. Integrating HIV clinical services into primary health care in Rwanda: a measure of quantitative effects. AIDS Care. 2009;21(5):608-14.

With the intensive scale-up of care and treatment for HIV in developing countries, some fear that intensified attention to HIV programmes may overwhelm health care systems and lead to declines in delivery of other primary health care. Few data exist that confirm negative or positive synergies on health care provision generally resulting from HIV-dedicated programs. Using a retrospective observational design Price and colleagues compare aggregate service data in Rwandan health facilities before and after the introduction of HIV care on selected measures of primary health care. The study tests the hypothesis that non-HIV care does not decrease after the introduction of basic HIV care. Overall, no declines were observed in reproductive health services, services for children, laboratory tests, and curative care. Statistically significant increases were found in utilization and provision of some preventive services. Multivariate regression, including introduction of HIV care and two important health care financing initiatives in Rwanda, revealed positive associations of all with observed increases. Introduction of HIV services was especially associated with increases in reproductive health. While hospitalization rates increased for the whole sample, declines were observed at health facilities that offered basic HIV care plus highly active antiretroviral therapy. The authors indicate that their results partially counter fears that HIV programs are producing adverse effects in non-HIV service delivery. Rather than leading to declines in other primary health care delivery, they say their findings suggest that the integration of HIV clinical services may contribute to increases.

Editors’ note: This study of 30 primary health centres that had at least 6 months experience offering basic HIV care, defined as voluntary counselling and testing, prevention of mother-to-child transmission services, and preventive therapy with cotrimoxasole, found positive synergies between HIV care and the delivery of other primary care services, particularly antenatal care. This study would be strengthened by consideration of outcome indicators, such as maternal mortality and incidence of congenital syphilis, rather than solely service utilisation indicators. The changes documented here occurred against a backdrop of two important nationally coordinated health care financing programmes that the researchers did try to take into account– the mutuelle de santé, Rwanda’s nationwide primary health insurance system, and performance based financing of health centres. Both of these programmes would be expected to increase uptake and improve outcomes.

Hanefeld J, Musheke M. What impact do Global Health Initiatives have on human resources for antiretroviral treatment roll-out? A qualitative policy analysis of implementation processes in Zambia. Hum Resour Health. 2009 Feb 10;7(1):8. [Epub ahead of print]

Since the beginning of the 21st century, development assistance for AIDS has increasingly been provided through Global Health Initiatives (GHI), specifically the United States Presidential Emergency Plan for AIDS Relief, the Global Fund to Fight HIV, TB and Malaria and the World Bank Multi-country AIDS Programme. Zambia, like many of the countries heavily affected by HIV in southern Africa, also faces a shortage of human resources for health. The country receives significant amounts of funding from GHIs for the large-scale provision of antiretroviral treatment through the public and private sector. This paper examines the impact of GHIs on human resources for antiretroviral treatment roll-out in Zambia, at national level, in one province and two districts. Hanefeld and Musheke undertook a qualitative policy analysis relying on in-depth interviews with more than 90 policy-makers and implementers at all levels. Findings show that while GHIs do not provide significant funding for additional human resources, their interventions have significant impact on human resources for health at all levels. While GHIs successfully retrain a large number of health workers, evidence suggests that GHIs actively deplete the pool of skilled human resources for health by recruiting public sector staff to work for GHI-funded nongovernmental implementing agencies. The secondment of GHI staff into public sector facilities may help alleviate immediate staff shortages, but this practice risks undermining sustainability of programmes. GHI-supported programmes and initiatives add significantly to the workload of existing public sector staff at all levels, while incentives including salary top-ups and overtime payments mean that antiretroviral treatment programmes are more popular among staff than services for non-focal diseases. Research findings suggest that GHIs need to actively mediate against the potentially negative consequences of their funding on human resources for health. Evidence presented highlights the need for new strategies that integrate retraining of existing staff with longer-term staff development to ensure staff retention. The study results show that GHIs must provide significant new and longer-term funding for additional human resources to avoid negative consequences on the overall provision of health care services and to ensure sustainability and quality of programmes they support.

Editors’ note: Zambia faces a severe shortage in human resources for health with the greatest need being for laboratory technicians, followed by pharmacists, doctors, nurses, and data monitors. There is rapid turnover of staff, high staff absenteeism, and unequal urban-rural distribution. At the time this research was conducted, the only targeted human resource intervention receiving any donor support was the rural retention scheme. Countries should require Global Health Initiatives to conduct human resource impact assessments. It is time to think seriously about the wisdom of addressing public sector human resources needs, in the interest of the long-term sustainability of antiretroviral treatment programmes.

Zolopa A, Andersen J, Powderly W, Sanchez A, Sanne I, Suckow C, Hogg E, Komarow L. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS ONE. 2009;4(5):e5575.

Optimal timing of antiretroviral therapy initiation for individuals presenting with AIDS-related opportunistic infections has not been defined. A5164 was a randomized strategy trial of “ early antiretroviral therapy”—given within 14 days of starting treatment for acute opportunistic infection versus “deferred antiretroviral therapy”—given after treatment for acute opportunistic infection is completed. Randomization was stratified by presenting opportunistic infections and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) >or=50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry opportunistic infections included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started antiretroviral therapy a median of 12 and 45 days after the start of treatment for opportunistic infections, respectively. AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early antiretroviral therapy arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27-0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30-0.92). The early antiretroviral therapy had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events. Early antiretroviral therapy resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred antiretroviral therapy. These results support the early initiation of antiretroviral therapy in patients presenting with acute AIDS-related opportunistic infections, absent major contraindications.

Editors’ note: Waiting to complete treatment for an opportunistic infection before initiating antiretroviral treatment in this USA/South Africa study was associated with a higher risk of HIV disease progression and/or death, with no safety or virological advantage. Concerns about toxicity, drug-drug interactions, immune reconstitution inflammatory syndrome, and adherence have made clinicians cautious about initiating antiretroviral treatment during treatment for opportunistic infections. However, as this study demonstrates, earlier antiretroviral treatment brings earlier improvement in immune responsiveness, which narrows the ‘window of vulnerability’ to additional HIV-related complications, preventing clinical progression.

Demeter LM, Jiang H, Mukherjee AL, Morse GD, Difrancesco R, Dicenzo R, Dykes C, Sista P, Bacheler L, Klingman K, Rinehart A, Albrecht M. A randomized trial of therapeutic drug monitoring of protease inhibitors in antiretroviral-experienced, HIV-1-infected patients. AIDS. 2009;23(3):357-68

Whether therapeutic drug monitoring of protease inhibitors improves outcomes in HIV-infected patients is controversial. Demeter and colleagues evaluated this strategy in a randomized, open-label clinical trial, using a normalized inhibitory quotient (NIQ), which incorporates drug exposure and viral drug resistance. NIQs </= 1 may predict poor outcome and identify patients who could benefit from dose escalation. Eligible patients had a viral load >/=1000 copies/ml on a failing regimen, and began a new protease inhibitor containing regimen at entry. All FDA-approved protease inhibitors available during the study recruitment (June 2002-May 2006) were allowed. One hundred and eighty-three participants with NIQ </= 1, on the basis of their week 2 protease inhibitor trough concentration and pre-entry drug resistance test, were randomized at week  4 to standard of care (SOC) or protease inhibitor dose escalation (therapeutic drug monitoring). The primary endpoint was change in log10 plasma HIV-1 RNA concentration from randomization to 20 weeks later. Ninety-one patients were randomized to standard of care and 92 to therapeutic drug monitoring. NIQs increased more in the therapeutic drug monitoring arm compared to standard of care (+69 versus +25%, P = 0.01). Despite this, therapeutic drug monitoring and standard of care arms showed no difference in outcome (+0.09 versus +0.02 log10, P = 0.17). In retrospective subgroup analyses, patients with less HIV resistance to their protease inhibitors benefited from therapeutic drug monitoring (P = 0.002), as did black and Hispanic patients (P = 0.035 and 0.05, respectively). Differences between black and white patients persisted when accounting for protease inhibitor susceptibility. There was no overall benefit of therapeutic drug monitoring. In post hoc subgroup analyses, therapeutic drug monitoring appeared beneficial in black and Hispanic patients, and in patients whose virus retained some susceptibility to the protease inhibitors in their regimen.

Editors’ note: Although the authors state that they compared differences between the therapeutic drug monitoring group and the standard of care group with respect to the primary endpoint (change in viral load after 20 weeks) in specific sub-groups of patients according to sex, race and ethnicity, number of protease inhibitors in the study regimen, and whether fos-amprenavir was used) no data are provided for women who constituted 13% of the study participants. This is another example of the ‘fugitive data issue’ that the Women and Trials movement has identified as problematic. Authors need to make an extra effort to publish these data, as not enough is known about sex differences in pharmacokinetics and pharmacodynamics.