HIV This Week

Evolutionary Dynamics of Complex Networks of HIV Drug-Resistant Strains: The Case of San Francisco.

Smith R, Okano J, Kahn J, Bodine E, Blower S. Science. 2010. Jan. [Epub ahead of print]

Over the past two decades, HIV resistance to antiretrovirals has risen to high levels in the wealthier countries of the world able to afford widespread treatment. The authors have gained insights into the evolution and transmission dynamics of ARV resistance by designing a biologically complex multistrain network model. Using this model, they traced the evolutionary history of antiretroviral resistance in San Francisco and predict the future dynamics. Using classification and regression trees, Smith and colleagues have identified the key immunologic, virologic, and treatment factors that increase antiretroviral resistance. Their modelling shows that 60% of the currently circulating antiretroviral-resistant strains in San Francisco are capable of causing self-sustaining epidemics, as each individual infected with one of these strains can cause on average more than one new resistant infection. It is possible that a new wave of antiretroviral-resistant strains that pose a significant threat to global public health is emerging.

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Editors’ note: These modellers predict that a wave of NNRTI- (non-nucleoside reverse transcriptase inhibitor) resistant strains will emerge over the next 5 years in San Francisco due to HIV transmission from untreated individuals. They also claim that if the reproduction number (the number of infections that one person transmits) of wild-type strains is reduced below one in resource-constrained settings (which would normally see an epidemic decline), self-sustaining epidemics of NNRTI-resistant strains could arise. Whether their model’s predictions are accurate or not remains to be seen but clearly increased investment in resistance monitoring around the world is warranted as we scale up to universal access to antiretroviral treatment for all.

Improved Virological Outcomes in British Columbia Concomitant with Decreasing Incidence of HIV Type 1 Drug Resistance Detection.

Gill V, Lima V, Wen Zhang, Wynhoven B, Yip B, Hogg R, Montaner J, and Harrigan R . Clinical Infectious Diseases. 2010. 50:98–105.

There have been limited studies evaluating temporal changes in the incidence of detection of drug resistance among human immunodeficiency virus type 1 (HIV-1) isolates and concomitant changes in plasma HIV load for treated individuals in a population-wide setting. Longitudinal plasma viral load and genotypic resistance data were obtained from patients receiving antiretroviral therapy from the British Columbia Drug Treatment Program from July 1996 through December 2008. A total of 24,652 resistance tests were available from 5422 individuals. The incidence of successful plasma viral load suppression and of resistance to each of 3 antiretroviral categories (nucleoside/nucleotide reversetranscriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors) was calculated for the population receiving therapy. There has been a drastic decrease in the incidence of new cases of HIV-1 drug resistance in individuals followed during 1996–2008. In 1997, the incidence rate of any newly detected resistance was 1.73 cases per 100 person-months of therapy, and by 2008, the incidence rate had decreased 112-fold, to 0.13 cases per 100 person-months of therapy. This decrease in the incidence of resistance has occurred at an exponential rate, with halftimes on the order of 2–3 years. Concomitantly, the proportion of individuals with plasma viral load suppression has increased linearly over time (from 64.7% with HIV RNA levels !50 copies/mL in 2000 to 87.0% in 2008; R2p0.97; P ! .001). The authors’ results suggest an increasing effectiveness of antiretroviral therapy at the populational level. The vast majority of treated patients in British Columbia now have either suppressed plasma viral load or drug-susceptible HIV-1, according to their most recent test results.

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Editors’ note: Rather than investigating the prevalence of transmitted drug resistance in the population or the prevalence of acquired drug resistance among people on treatment, these investigators, who were uniquely placed to do so, assessed the incidence of drug resistance over a 12-year period. They found exponential decreases in the incidence rate of drug resistance, including NNRTI (non-nucleoside reverse transcriptase inhibitor) resistance (40-fold decrease), despite increases in annual and cumulative exposure to antiretroviral drugs. These authors conclude that efforts to improve accessibility to antiretroviral treatment have the potential to greatly reduce HIV-1 levels in a population without increasing the risk of drug resistance.

Response to planned treatment interruptions in HIV infection varies across childhood

Paediatric European Network for Treatment of AIDS . AIDS. 2010. 24:231-41.

The aim of this study was to evaluate clinical, immunological, and virological consequences of CD4-guided antiretroviral therapy planned treatment interruptions compared with continuous therapy in children with chronic HIV infection in the Paediatric European Network for Treatment of AIDS 11 trial. This was a multicentre, 72-week, open, randomized, phase II trial. One hundred and nine children with HIV-RNA below 50 copies/ml and CD4% of at least 30% (2-6 years) or at least 25% and CD4 cell count of at least 500 cells/microl (7-15 years) were randomized to continuous therapy (53) or planned treatment interruptions (56). In planned treatment interruptions, antiretroviral therapy was restarted if confirmed CD4% was less than 20% or more than 48 weeks had been spent off antiretroviral therapy. The primary outcome was Centers for Disease Control and Prevention (CDC) stage C event, death, or CD4% less than 15% (and CD4 cell count less than 200 cells/microl for children aged 7-15 years). At baseline, median (interquartile range) age was 9 (6-12) years, CD4% 37% (33-41), CD4 cell count 966 (793-1258) cells/microl, nadir CD4% before combination antiretroviral therapy 18% (10-27), time on antiretroviral therapy 6 (3-6) years, and 26% were CDC stage C. After median (range) 130 (33-180) weeks of follow-up, 4 versus 48% of time was spent off antiretroviral therapy in continuous therapy and planned treatment interruptions, respectively. No child died or had a new CDC stage C event; one (2%) continuous therapy versus four (7%) planned treatment interruptions children had a primary outcome based on CD4%/cell count (P = 0.2). Lower nadir CD4% predicted faster CD4% decline after stopping antiretroviral therapy. Younger age and higher nadir CD4% predicted being off ART for at least 48 weeks and better CD4% recovery following planned treatment interruptions. In this first paediatric trial of planned treatment interruption, there were no serious clinical outcomes. Younger children had better CD4% recovery after planned treatment interruptions. Immunology substudies and long-term follow-up in Paediatric European Network for Treatment of AIDS 11 trial are ongoing. Further research into the role of treatment interruption in children is required, particularly, as guidelines now recommend early antiretroviral therapy for all infected infants.

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Editors’ note: After starting antiretroviral treatment, children have a greater potential for immune regeneration than do adults because the thymus is more active in childhood. Furthermore, the risk-benefit balance of lifelong continuous treatment versus planned treatment interruptions in vertically HIV-infected children may be different than for adults, considering the risks of long-term drug toxicity and viral resistance. The encouraging results of this PENTA II pilot study, the first planned treatment interruption trial to take place in children, support continuation of two large treatment interruption trials ongoing in Africa. These are the CHER trial in South Africa studying 400 infants starting antiretroviral treatment before 12 weeks of age and stopping at first or second birthday, and the Bana trial in Botswana of 600 children which has a similar design to PENTA II with different CD4% thresholds for stopping and restarting. Given that it is recommended that all infants start antiretroviral treatment as soon as HIV infection is diagnosed, learning whether planned treatment interruptions are a good idea in children is an important clinical research question.

Utility of a Point-of-Care Malaria Rapid Diagnostic Test for Excluding Malaria as the Cause of Fever among HIV-Positive Adults in Rural Rakai, Uganda.

Mills L, Kagaayi J, Nakigozi G, Galiwango R, Ouma J, Shott J, Ssempijja V, Gray R, Wawer M, Serwadda D, Quinn T, and Reynolds S. Am. J. Trop. Med. Hyg. 2010. 82:145-147.

Mills and colleagues compared results of a malaria rapid diagnostic test (Binax Now ® Malaria, Binax-M, Inverness Medical Innovations, Inc., Waltham, MA) performed at rural mobile clinics in Uganda by clinicians evaluating febrile adult HIV patients to thick smear evaluated at a central laboratory by trained microscopists. Two hundred forty-six samples were analyzed, including 14 (5.7%) which were thick-smear positive for falciparum malaria. Sensitivity of Binax-M compared with thick smear was 85.7% (95% CI: 57.2–98.2), specificity 97.8% (95% CI: 94.9–99.3), positive and negative predictive values were 70.6% (95% CI: 44.0–89.7) and 99.1% (95% CI: 96.8–99.9), respectively. The rapid diagnostic test accurately ruled malaria “in or out” at the point-of-care, facilitating appropriate clinical management and averting unnecessary anti-malarial therapy.

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Editors’ note: Through a PEPFAR-funded mobile HIV clinic programme, most participants in this study in a falciparum malaria endemic district in Uganda had received insecticide treated bed nets, cotrimoxasole prophylaxis regardless of CD4 count, and antiretroviral treatment if their CD4 counts fell below 250 cells/ µ l. With malaria suspected in 41.5% of general out-patient visits in this district, use of this point-of-care test in people living with HIV who presented with fever allowed health care providers to focus on other urgent causes of fever. The test had a high negative predictive value, meaning that a negative test was highly likely to mean that the person did not have malaria.

Recurrent TB: relapse or reinfection? The effect of HIV in a general population cohort in Malawi.

Crampin AC, Mwaungulu JN, Mwaungulu FD, Mwafulirwa DT, Munthali K, Floyd S, Fine PE, Glynn JR. AIDS. 2010 Jan 28;24(3):417-26

The aim of the study was to estimate rates of recurrent tuberculosis due to reinfection and relapse, by HIV status, in a general population. A long-term cohort study was conducted in Karonga district, rural Malawi. All tuberculosis patients with culture-proven disease in Karonga district were followed up after treatment. HIV testing was offered and all Mycobacterium tuberculosis isolates were fingerprinted using IS6110 RFLP. Fingerprints from initial and recurrent disease episodes were compared to distinguish relapse and reinfection: a second episode was considered a relapse if the fingerprint was identical or differed by only 1-4 bands and was the first occurrence of that pattern in the population. Rates of and risk factors for recurrence, reinfection disease, and relapse were estimated using survival analysis and Poisson regression. Five hundred and eighty-four culture-positive episodes of tuberculosis were diagnosed and treatment was completed during 1995-2003 in patients with known HIV status; 53 culture-positive recurrences occurred by May 2005. Paired fingerprints were available for 39 of these. Reinfections accounted for 1/16 recurrences in HIV-negative and 12/23 in HIV-positive individuals. Rates of relapse were similar in HIV-positive and HIV-negative individuals. Using multiple imputation to allow for missing fingerprint information, the rate of reinfection disease in HIV-positive individuals was 2.2/100 person-years, and in HIV-negative individuals 0.4/100 person-years. HIV increases the rate of recurrent tuberculosis in this setting by increasing the rate of reinfection disease, not relapse.

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Editors’ note: It appears from this and other studies that a second bout of tuberculosis (TB) in an HIV-negative person in most settings is most likely to be due to relapse and may reflect overall programme effectiveness in treating TB. Relapse rates following successful completion of treatment are highest in the first 6 months off treatment. Although numbers were small, relapse rates in this study were encouragingly similar for HIV-negative and HIV-positive people. The story was much different for re-infection with a rate ratio of 6.3 (1.3-31.5, p=0.02) comparing HIV-positive and HIV-negative individuals. That re-infection occurs at all among HIV-negative people begs the question: if natural infection does not always prevent re-infection, is there still hope for a TB vaccine, at least for some people? The higher risk of re-infection in HIV-positive people, none of them on antiretroviral treatment, suggests that HIV may directly influence the risk of re-infection, increase the risk of development of disease, and/or increase the risk of exposure to other TB strains in health care settings. It is important to untangle the contribution of each of these and to see if antiretroviral treatment scale-up to all HIV-positive patients with TB, along with environmental controls in TB and HIV clinics, can reduce the risk of re-infection and associated high mortality for people living with HIV.

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

DART Trial Team. The Lancet, Early Online Publication, 9 December 2009 [Epub ahead of print]

HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving antiretroviral therapy had an important long-term effect on clinical outcomes in Africa. In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, antiretroviral therapy-naive, HIV-infected adults with CD4 counts less than 200 cells per muL starting antiretroviral therapy were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the laboratory and clinical monitoring group, results were available to clinicians; in the clinically driven monitoring group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line antiretroviral therapy after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per muL (laboratory and clinical monitoring only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. Two participants assigned to clinically driven monitoring and three to laboratory and clinical monitoring were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years’ follow-up. 459 (28%) participants receiving clinically driven monitoring versus 356 (21%) laboratory and clinical monitoring had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on antiretroviral therapy, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving clinically driven monitoring versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). Antiretroviral therapy can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of antiretroviral therapy to guide the switch to second-line treatment.

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Editors’ note: These findings, presented at the International AIDS Society conference in Cape Town in July 2009 are fully described here, complementing the excellent film produced by Tom Gibb (http://www.youtube.com/MRCcomms#p/u/1/MSyFmbiR-Hc). The results of this trial, designed to determine whether clinician monitoring of signs and symptoms without knowledge of CD4 count was not inferior to similar monitoring with knowledge of CD4 test results, suggest that once eligibility for antiretroviral treatment is determined, clinically driven monitoring holds the fort well for the first 2 years of treatment, freeing up resources and allowing extension of treatment access to more remote areas with no laboratory infrastructure.

McCarthy K, Chersich MF, Vearey J, Meyer-Rath G, Jaffer A, Simpwalo S, Venter WD. Int J STD AIDS. 2009 20:858-62.

Foreigners, including displaced persons, often have limited health-care access, especially to HIV services. Outcomes of antiretroviral therapy (ART) in South Africans and foreigners were compared at a Johannesburg non-governmental clinic. Records were reviewed of 1297 adults enrolled between April 2004 and March 2007 (568 self-identified foreigners, 431 South Africans citizens and 298 with unknown origin). Compared with citizens, foreigners had fewer hospital admissions (39%, 90/303 versus 51%, 126/244; P < 0.001), less missed appointments for antiretroviral therapy initiation (20%, 39/200 versus 25%, 51/206; P < 0.001), faster median time to antiretroviral therapy initiation (14 versus 21 days, P = 0.008), better retention in care (88%, 325/369 versus 69%, 155/226; P < 0.001) and lower mortality (2.5%, 14/568 versus 10%, 44/431; P < 0.001) after 426 person-years. In logistic regression, after controlling for baseline CD4 count and tuberculosis status, foreigners were 55% less likely to fail antiretroviral therapy than citizens (95% CI = 0.23-0.87). These findings support United Nations High Commissioner for Refugees recommendations that antiretroviral therapy should not be withheld from displaced persons.

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Editors’ note: South Africa at the end of 2007 had the world’s largest number of pending asylum applications and was second only to the United States of America in annual new asylum claims. The level of undocumented migrants is much higher. The findings from this study demonstrate that foreigners were about half as likely to fail antiretroviral treatment as citizens, despite having lower baseline median CD4 cell counts and being subject to significant hurdles in accessing and staying in care. This strongly supports the argument that foreigners should be included in the ‘right to access antiretroviral treatment for all.  

Effectiveness of paediatric antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis.

Ciaranello AL, Chang Y, Margulis AV, Bernstein A, Bassett IV, Losina E, Walensky RP. Clin Infect Dis. 2009;49:1915-27.

Responses to antiretroviral therapy (ART) among human immunodeficiency virus (HIV)-infected children in resource-limited settings have recently been reported, but outcomes vary. The authors sought to derive pooled estimates of the 12-month rate of virologic suppression (HIV RNA, <400 copies/mL) and gain in CD4 cell percentage (DeltaCD4%) for children initiating antiretroviral therapy in resource-limited settings. Ciaranello et al conducted a systematic review and meta-analysis of published reports of HIV RNA and CD4 outcomes for treatment-naive children aged 0-17 years old by means of the Medline, EMBASE (Excerpta Medica Database), and LILACS (Latin American and Caribbean Health Sciences Literature) electronic databases and the Cochrane Clinical Trials Register. Pooled estimates of the reported proportion with HIV RNA <400 copies/mL and DeltaCD4% after 12 months of antiretroviral therapy were derived using patient-level estimates and fixed- and random-effects models. To approximate intention-to-treat analyses, in sensitivity analyses children with missing 12-month data were assumed to have HIV RNA>400 copies/mL or DeltaCD4% of zero. In patient-level estimates after 12 months of antiretroviral therapy, the pooled proportion with virologic suppression was 70% (95% confidence interval [CI], 67%-73%); the pooled DeltaCD4% was 13.7% (95% CI, 11.8%-15.7%). Results from the fixed- and random-effects models were similar. In approximated intention-to-treat analyses, the pooled estimates decreased to 53% with virologic suppression (95% CI, 50%-55%) and to a DeltaCD4% of 8.5% (95% CI, 5.5%-11.4%). Pooled estimates of reported virologic and immunologic benefits after 12 months of antiretroviral therapy among HIV-infected children in resource-limited settings are comparable with those observed among children in developed settings. Consistency in reporting on reasons for missing data will aid in the evaluation of antiretroviral therapy outcomes in resource-limited settings.

Full text: 1

Editors’ note: Treatment outcomes for treatment-naïve children after 1 year are similar in resource-poor settings as they are in the United States of America and Europe, despite advanced stages of HIV disease at initiation of antiretroviral treatment, substantial barriers to service delivery, and predominantly non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. This is great news from this first study to provide pooled estimates of the virological suppression rate and change in CD4 percentage in children in countries with emerging or developing economies. These findings have particular importance for the estimated 90% of children living with HIV who reside in resource-limited settings and should spur on the movement to treat all children living with HIV.

Six-month gain in weight, height, and CD4 predict subsequent antiretroviral treatment responses in HIV-infected South African children.

Yotebieng M, Van Rie A, Moultrie H, Meyers T. AIDS. 2010 24:139-46.

The aim of the study was to construct percentile curves for 6-month gain in weight, height, CD4 cell count, and CD4 percentage (CD4%) in children initiating antiretroviral therapy, and to assess the association between lower percentiles and subsequent antiretroviral therapy responses. A cohort of 1394 HIV-infected children initiating antiretroviral therapy between April 2004 and March 2008, Johannesburg, South Africa were enrolled. The generalized additive model for location, scale, and shape was used to construct percentile curves for 6-month gain in weight, height, CD4 cell count, and CD4%. Cox proportional models were used to assess the association between lower percentiles of each distribution and death, virological suppression, and treatment failure between 6 to 36 months post-antiretroviral therapy initiation. Lower percentiles for gain in weight, CD4, and CD4% count after 6 months of antiretroviral therapy, but not height, were associated with poor subsequent treatment outcomes independent of baseline characteristics, with increasing strength of association as percentiles decreased. Age-specific 6-month post-antiretroviral therapy weight gain in this cohort was substantially higher compared with 6-month weight gain in non-HIV-infected American children of the Fels Institute cohort and the attained weight-for-age at 6 months post- antiretroviral therapy plotted on WHO weight-for-age growth charts were not associated with subsequent treatment outcomes. Gain in CD4% in the first 6 months of antiretroviral therapy was the best predictor of poor subsequent antiretroviral therapy outcomes. In areas with limited access to CD4%, weight gain post- antiretroviral therapy using these newly developed reference distributions for HIV-infected children on antiretroviral therapy is a good alternative to CD4%, and clearly superior to the commonly used ‘Road-to-Health’ weight-for-age charts.

Abstract only: 1 

Editors’ note: A third of children vertically infected do not survive to their first birthday and more than half die before age 2. When children start antiretroviral treatment, it is important to monitor their clinical improvement to assess whether they are benefitting. This innovative study developed HIV-specific weight gain reference curves that can be used by health workers in settings without CD4 percentage laboratory tests to identify which children on treatment are likely to be virologically suppressed and which ones are at higher risk for treatment failure and subsequent death. These reference curves should be tested in other settings and adjusted as necessary to develop international weight gain reference curves for children starting antiretroviral treatment. 

“Talkin’ about a revolution”: How electronic health records can facilitate the scale-up of HIV care and treatment and catalyze primary care in resource-constrained settings.

Braitstein P, Einterz RM, Sidle JE, Kimaiyo S, Tierney W. J Acquir Immune Defic Syndr. 2009 Nov;52(S1).

Health care for patients with HIV infection in developing countries has increased substantially in response to major international funding. Scaling up treatment programs requires timely data on the type, quantity, and quality of care being provided. Increasingly, such programs are turning to electronic health records to provide these data. The authors describe how a medical school in the United States and another in Kenya collaborated to develop and implement an electronic health records system in a large HIV care program in western Kenya. These data were used to manage patients, providers, and the program itself as it grew to encompass 18 sites serving more than 90,000 patients. Lessons learned have been applicable beyond HIV to include primary care, chronic disease management, and community-based health screening and disease prevention programs. Electronic health records will be key to providing the highest possible quality of care for the funds developing countries can commit to health care. Public, private, and academic partnerships can facilitate the development and implementation of electronic health records in resource-constrained settings.

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Editors’ note: Quality health care depends, among other things, on collecting, analysing, and using timely health information. Well managed health information management systems can help programme managers plan deployment of personnel, avoid drug stockouts, and maximise resource use. But, first and foremost, meeting clinicians’ requirements for complete and accurate data is key to ensuring high-quality care for patients. Electronic medical records using unique identifiers while protecting patient confidentiality and data security help coordinate care across multiple venues and specialities. Patients can be notified quickly of drug recalls or eligibility for novel treatments and can use their laminated personal card to access care throughout the health system. Investment in electronic health records for patients in antiretroviral treatment programmes is reaping benefits in low- and middle-income countries that are expanding data capture and management to support the scale up of efficient, effective clinical services for other conditions. We really are “talkin’ about a revolution”!

Nash D, Elul B, Rabkin M, Tun M, Saito S, Becker M, Nuwagaba-Biribonwoha H. J Acquir Immune Defic Syndr. 2009 Nov;52(S2).

Program monitoring and evaluation has the potential to be a cornerstone of health systems strengthening and of evidence-informed implementation and scale-up of HIV-related services in resource-limited settings. The authors discuss common challenges to monitoring and evaluation systems used in the rapid scale-up of HIV services as well as innovations that may have relevance to systems used to monitor, evaluate, and inform health systems strengthening. These include (1) Web-based applications with decentralized data entry and real-time access to summary reporting; (2) timely feedback of information to site and district staff; (3) site-level integration of traditionally siloed program area indicators; (4) longitudinal tracking of program and site characteristics; (5) geographic information systems; and (6) use of routinely collected aggregate data for epidemiologic analysis and operations research. Although conventionally used in the context of vertical programs, these approaches can form a foundation on which data relevant to other health services and systems can be layered, including prevention services, primary care, maternal-child health, and chronic disease management. Guiding principles for sustainable national monitoring and evaluation systems include country-led development and ownership, support for national programs and policies, interoperability, and employment of an open-source approach to software development.

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Editors’ note: This article starts with a diagnosis of the challenge of providing timely and useful feedback to key staff at individual health facilities when information is hand tallied from paper-based sources and reported up to district, regional, national, and international agencies on schedules that reflect the latter’s needs. When the objective is continuous improvement of quality, scale, equity, and impact of services, the benefits of web-based real-time systems using solar powered mobile phones for data entry (such as Rwanda is developing) are evident. Overcoming silos in HIV monitoring and evaluation systems, each one designed for its own programme (e.g. antiretroviral treatment, prevention of mother-to-child transmission, voluntary counselling and testing), is key to moving forward to systems that integrate disease- or programme-specific data within broader primary care.

Antiretroviral therapy in antenatal care to increase treatment initiation in HIV-infected pregnant women: a stepped-wedge evaluation.

Killam WP, Tambatamba BC, Chintu N, Rouse D, Stringer E, Bweupe M, Yu Y, Stringer JS. AIDS. 2010 2; 24:85-91.

The objective of this study was to evaluate whether providing antiretroviral therapy (ART) integrated in antenatal care clinics resulted in a greater proportion of treatment-eligible women initiating antiretroviral therapy during pregnancy compared with the existing approach of referral to antiretroviral therapy. The evaluation used a stepped-wedge design and included all HIV-infected, antiretroviral therapy-eligible pregnant women in eight public sector clinics in Lusaka district, Zambia. The main outcome indicators were the proportion of treatment-eligible women enrolling into HIV care while pregnant and within 60 days of HIV diagnosis and proportion initiating antiretroviral therapy during pregnancy. Adjusted odds ratios (AORs) and confidence intervals (CIs) for enrolment and initiation proportions were estimated through a logistic regression model accounting for clinical site cluster and time effects. Between 16 July 2007 and 31 July 2008, 13 917 women started antenatal care more than 60 days before the intervention rollout and constituted the control cohort; 17 619 started antenatal care after antiretroviral therapy integrated into antenatal care and constituted the intervention cohort. Of the 1566 patients found eligible for antiretroviral therapy, a greater proportion enrolled while pregnant and within the 60 days of HIV diagnosis in the intervention cohort (376/846, 44.4%) compared with the control cohort (181/716, 25.3%), adjusted odds ratio 2.06, 95% CI (1.27-3.34); and initiated antiretroviral therapy while pregnant in the intervention cohort (278/846, 32.9%) compared with the control cohort (103/716, 14.4%), adjusted odds ratio 2.01, 95% CI (1.37-2.95). An integrated antiretroviral therapy in antenatal care strategy doubled the proportion of treatment-eligible women initiating antiretroviral therapy while pregnant.

For access to abstract click here: 1

Editors’ note: This step-wedged evaluation design had all 8 participating clinics starting to collect data at the same time while providing the standard of care, i.e. referral to antiretroviral treatment services. Then one by one, each clinic crossed over to the intervention arm with antiretroviral services being provided in the antenatal care setting. This design allowed each clinic to act as its own control, providing patients to both arms, while also controlling for time trends by allowing comparisons across clinics at fixed points in time. Even though the treatment clinics were located on the same premises as the antenatal care clinics and local peer educators provided education and support to eligible women and offered to escort them to the treatment clinic, the percentage of treatment-eligible pregnant women initiating antiretroviral treatment more than doubled when antiretroviral treatment services were integrated into antenatal care. The lessons from this study can be applied to tuberculosis clinics and other services. Locating services together only goes so far in meeting patient needs and integration can make a big difference to uptake .

Novel approaches to inhibiting HIV-1 replication.

Adamson CS, Freed EO. 2009 Antiviral Res. Sep [Epub ahead of print]

Considerable success has been achieved in the treatment of HIV-1 infection, and more than two-dozen antiretroviral drugs are available targeting several distinct steps in the viral replication cycle. However, resistance to these compounds emerges readily, even in the context of combination therapy. Drug toxicity, adverse drug-drug interactions, and accompanying poor patient adherence can also lead to treatment failure. These considerations make continued development of novel antiretroviral therapeutics necessary. In this article, the authors highlight a number of steps in the HIV-1 replication cycle that represent promising targets for drug discovery. These include lipid raft microdomains, the RNase H activityof the viral enzyme reverse transcriptase, uncoating of the viral core, host cell machinery involved in the integration of the viral DNA into host cell chromatin, virus assembly, maturation, and budding, and the functions of several viral accessory proteins. The authors discuss the relevant molecular and cell biology, and describe progress to date in developing inhibitors against these novel targets.

For abstract access click here: 1

Editors’ note: Once inside the cell, HIV takes advantage of host cell factors and pathways, harnessing our machinery to promote its own replication. Having described the HIV life cycle, this article briefly reviews the classes of drugs that we currently have (more than 20 antiretroviral drugs have been licensed to date): entry inhibitors (fusion inhibitors and CCR5 antagonists), reverse transcriptase inhibitors (non-nucleoside and nucleoside, i.e. NNRTI and NRTI), protease inhibitors, and integrase inhibitors. Then, accompanied by many colourful figures, the authors present an array of potential new therapeutic targets that include viral-host protein interactions or cellular targets. It will be a challenge for virology and biology (chemical, structural, molecular, and cell) to determine whether we can block HIV’s use of these interactions or cellular targets for multiple steps of its own replication without creating toxicity for us, since we need these proteins and cellular factors for a variety of our own functions. 

Hill A, van der Lugt J, Sawyer W, Boffito M. AIDS. 2009; 23:2237-45

Ritonavir has been evaluated at boosting doses of 50-800 mg daily with seven protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir, saquinavir and tipranavir. Minimizing the boosting dose of ritonavir could improve tolerability and lower costs. A MEDLINE search identified 17 phamacokinetic trials using different ritonavir doses with protease inhibitors. The dose of ritonavir used was correlated with plasma levels of each boosted protease inhibitor. For the five pharmacokinetic trials of lopinavir/ritonavir, a meta-analysis was used to estimate the effects of lopinavir dose versus ritonavir dose on lopinavir pharmacokinetics. Saquinavir, fosamprenavir and darunavir were boosted equally well by lower (50-100 mg) versus higher doses of ritonavir. Indinavir, tipranavir and lopinavir were boosted more by higher ritonavir doses. Data on atazanavir were inconclusive. The ritonavir dose-dependence of boosting effects did not correlate with their bioavailability or their effects on ritonavir plasma levels. Atazanavir and indinavir raised plasma ritonavir levels by 69-72%, whereas saquinavir had no effects on ritonavir. Darunavir, lopinavir, tipranavir and fosamprenavir all lowered ritonavir plasma levels. For the meta-analysis of lopinavir/ritonavir trials, the 200/150 mg twice daily (b.i.d.) dose of lopinavir/ritonavir (one Meltrex 200/50 mg tablet and one ritonavir 100 mg b.i.d.) showed lopinavir area under the curve and minimum concentration similar to the standard 400/100 mg b.i.d. dose. It may be possible to use three protease inhibitors (saquinavir, amprenavir and darunavir) with lower doses of ritonavir. A 200/150 mg b.i.d. dose of lopinavir/ritonavir could lower costs while maintaining very similar lopinavir plasma levels to the standard dose. New pharmacoenhancer drugs may need to be used at different doses to boost different antiretrovirals.

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Editors’ note: A boosted protease inhibitor plus two nucleoside analogues (NRTIs) are recommended by WHO for second line antiretroviral treatment, with atazanavir and lopinavir being the preferred options. For boosted protease inhibitors, an optimal safety profile depends on both the choice of protease inhibitor and the lowest dose of ritonavir possible. The dose-ranging pharmacokinetic trials that are reported in the public domain here suggest that the pharmacokinetics of lopinavir are highly dependent on the dose of ritonavir used, as well as the lopinavir dose. This suggests that a crossover dose-ranging trial of lopinavir/ritonavir would help determine whether 400/100 mg versus 200/150 mg doses, for example, provide the optimum pharmacokinetics with lowest toxicity.

Gender asymmetry in healthcare-facility attendance of people living with HIV/AIDS in Burkina Faso.

Bila B, Egrot M. Soc Sci Med. 2009; 69:854-61

Anthropological research in Burkina Faso indicates that more HIV-positive women than HIV-positive men are attending care facilities for people living with HIV and accessing antiretroviral medicine. This article, situated in the field of study of interactions between gender and AIDS, offers a description of this asymmetry and an anthropological analysis of the socio-cultural determinants, through analysis of data from ethnographic research among people living with HIV and health actors. Examining social representations of femininity and masculinity in Burkinabe society and the organisation of the healthcare system in connection with gender shed light on the decision-making processes of both sexes around therapeutic choices and the itinerary of care. On the one hand, the social values attached to femininity, maternity and the status of wife create conditions for women that favour their attendance at care facilities for people living with HIV and encourage a widespread practice where wives take the place of their husbands in healthcare queues. Moreover, health policies and the effects of women’s empowerment within the healthcare system strengthen women’s access to health services. On the other hand, representations of masculinity are fully implicated in the cultural construction of men’s reluctance to attend care facilities for people living with HIV. The values associated with this masculinity cause men to run great health, economic and social risks, not only for themselves, but also for their wives and children. By better understanding the interaction between gender, the experience of HIV and the institutional organisation of healthcare, we can identify ways to reduce men’s reluctance to attend care facilities for people living with HIV and improve both prevention and treatment-oriented programmes.

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Editors’ note: This thoughtful article is an interesting read. Although the effects of gendered systems in sub-Saharan Africa create socioeconomic disadvantage and vulnerability for women compared to men, men are caught up in representations of masculinity that do not allow them to overcome their feelings of shame to seek care. These feelings centre both on having HIV infection and on needing external support for food, medicine and school supplies. In contrast, women’s feelings of obligation to be in good health so as to care for their children now and over the long-term motivate them to seek treatment, food, and school supply support readily at health care facilities. The result is that 2 men are followed clinically for every 3 to 6 women despite equivalent HIV prevalence. The solution is not separate service provision, although food support could be accessed at non-HIV care settings using vouchers, and is likely multi-faceted. Awareness raising focused on encouraging men living with HIV to value their social responsibility to their families and seek care might be a good start. 

Evaluation of a dried blood spot HIV-1 RNA program for early infant diagnosis and viral load monitoring at rural and remote healthcare facilities.

Lofgren SM, Morrissey AB, Chevallier CC, Malabeja AI, Edmonds S, Amos B, Sifuna DJ, von Seidlein L, Schimana W, Stevens WS, Bartlett JA, Crump JA. AIDS. 2009 23(18):2459-66.

Lofgren and colleagues set out to assess technical and operational performance of a dried blood spot-based HIV-1 RNA service for remote healthcare facilities in a low-income country. A method comparison and operational evaluation of dried blood spot RNA against conventional tests for early infant diagnosis of HIV and HIV RNA quantitation under field conditions in Tanzania was conducted. Dried blood spots were prepared and plasma was frozen at -80 degrees C. Dried blood spots were mailed and plasma couriered to a central laboratory for testing using the Abbott m2000 system. Infant diagnosis dried blood spots were also tested for HIV-1 DNA by ROCHE COBAS AmpliPrep/COBAS TaqMan System. Results of dried blood spot RNA were compared with conventional tests; program performance was described. Among 176 infant diagnosis participants, using a threshold of at least 1000 copies/ml, sensitivity and specificity of dried blood spot versus plasma RNA were 1.00 and 0.99, and of dried blood spot RNA versus dried blood spot DNA were 0.97 and 1.00. Among 137 viral load monitoring participants, when plasma and dried blood spot RNA were compared, r value was 0.9709; r value was 0.9675 for at least 5000 copies/ml but was 0.7301 for less than 5000 copies/ml. The highest plasma RNA value at which dried blood spot RNA was not detected was 2084 copies/ml. Median (range) turnaround time from sample collection to result receipt at sites was 23 (4-69) days. The Tanzania mail service successfully transmitted all dried blood spot and results between sites and the central laboratory. Under program conditions in Tanzania, dried blood spot provided HIV-1 RNA results comparable to conventional methods to remote healthcare facilities. The authors propose dried blood spot RNA testing as an alternative to liquid plasma for HIV-1 RNA services in remote areas

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Editors’ note: In this study, the weekly cost of mailing dried blood spot specimens from healthcare facilities to the central laboratory was 6$ compared to a weekly ground transport of frozen plasma samples on dry ice of 515$. The excellent sensitivity and specificity results for paediatric HIV diagnosis reported for dried blood spot specimens here, combined with a reasonable turnaround time for results in the absence of electronic or fax communications, suggests that cost-effectiveness analyses should be quickly undertaken. The earlier that infants with HIV infection are diagnosed, the sooner they can be placed on treatment .

Smith DM, May SJ, Pérez-Santiago J, Strain MC, Ignacio CC, Haubrich RH, Richman DD, Benson CA, Little SJ. AIDS. 2009; 23:2151-8.

To develop less costly methods to virologically monitor patients receiving antiretroviral therapy, the authors evaluated methods that use pooled blood samples and quantitative information available from viral load assays to monitor a cohort of patients on first-line antiretroviral therapy for virologic failure. They evaluated 150 blood samples collected after 6 months of therapy from participants enrolled in a San Diego primary infection program between January 1998 and January 2007. Samples were screened for virologic failure with individual viral load testing, 10 x 10 matrix pools and minipools of five samples. For the pooled platforms (matrix and minipools), the authors used a search and retest algorithm based on the quantitative viral load data to resolve samples that remained ambiguous for virologic failure. Viral load thresholds were more than 500 and more than 1500 copies/ml for the matrix and more than 250 and more than 500 copies/ml for the minipool. Efficiency, accuracy and result turnaround times were evaluated. Twenty-three percent of cohort samples were detectable at more than 50 HIV RNA copies/ml. At an algorithm threshold of more than 500 HIV RNA copies/ml, both minipool and matrix methods used less than half the number of viral load assays to screen the cohort, compared with testing samples individually. Both pooling platforms had negative predictive values of 100% for viral loads of more than 500 HIV RNA copies/ml and at least 94% for viral loads of more than 250 HIV RNA copies/ml. In this cohort, both pooling methods improved the efficiency of virologic monitoring over individual testing with a minimal decrease in accuracy. These methods may allow for the induction and sustainability of the virologic monitoring of patients receiving antiretroviral therapy in resource-limited settings.

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Editors’ note: Pooling strategies mix 5, 10, or more samples together for testing. If the pool is positive then each sample in the pool is tested to see which one(s) is (are) responsible. Viral load monitoring for patients on antiretroviral treatment is not recommended or performed in most resource-limited settings where the focus has been on getting more people in need on treatment. Adaptation of assays in current clinical use for settings with diverse HIV subtypes would allow the kinds of efficiency gains described here. The objective would be improved clinical outcomes and limits on the development of drug resistance.  

Isoniazid preventive therapy for people living with HIV: public health challenges and implementation issues.

Aït-Khaled N, Alarcon E, Bissell K, Boillot F, Caminero JA, Chiang CY, Clevenbergh P, Dlodlo R, Enarson DA, Enarson P, Ferroussier O, Fujiwara PI, Harries AD, Heldal E, Hinderaker SG, Kim SJ, Lienhardt C, Rieder HL, Rusen ID, Trébucq A, Van Deun A, Wilson N. Int J Tuberc Lung Dis. 2009 ;13:927-35.

Isoniazid preventive therapy is recognised as an important component of collaborative tuberculosis and human immunodeficiency virus (HIV) activities to reduce the burden of tuberculosis in people living with HIV. However, there has been little in the way of isoniazid preventive therapy implementation at country level. This failure has resulted in a recent call to arms under the banner title of the ‘Three I’s’ (infection control to prevent nosocomial transmission of tuberculosis in health care settings, intensified tuberculosis case finding and isoniazid preventive therapy). The authors review the background of isoniazid preventive therapy. They discuss the important challenges of isoniazid preventive therapy in people living with HIV, namely responsibility and accountability for the implementation, identification of latent tuberculosis infection, exclusion of active tuberculosis and prevention of isoniazid resistance, length of treatment and duration of protective efficacy. The authors also highlight several research questions that currently remain unanswered and offer practical suggestions about how to scale up isoniazid preventive therapy in the field, including the need to integrate isoniazid preventive therapy into a package of care for people living with HIV, the setting up of operational projects with the philosophy of ‘learning while doing’, the development of flow charts for eligibility for isoniazid preventive therapy, the development and implementation of care prior to antiretroviral treatment, and finally issues around procurement, distribution, monitoring and evaluation. The authors support the implementation of isoniazid preventive therapy, but only if it is done in a safe and structured way. There is a definite risk that ‘sloppy’ isoniazid preventive therapy will be inefficient and, worse, could lead to the development of multidrug-resistant tuberculosis, and this must be avoided at all costs.

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Editors’ note: Have you wondered why TB prophylaxis with isoniazid for people living with HIV is not getting the traction it deserves? This clear, straight to the heart of the matter article underscores the challenges of implementing isoniazid preventive therapy (IPT). These include defining clearly who is responsible, determining who should receive it, excluding active TB and preventing isoniazid resistance, and enhancing the duration of protective efficacy. Among the practical suggestions for scaling up IPT is its integration into the package of pre-antiretroviral treatment care. Pre-ART care can include regular checks of clinical status, CD4 counts, cotrimoxasole preventive therapy (CPT), nutritional support or guidance, family planning, counselling and provision of HIV prevention tools, and insecticide treated bed nets to prevent malaria. National AIDS programmes and national TB programmes need to work together to include IPT in pre-ART care and ensure the conduct of quality monitoring and operational research designed to detect and address problems quickly to improve programme performance.

Universal HIV testing of infants at immunization clinics: an acceptable and feasible approach for early infant diagnosis in high HIV prevalence settings.

Rollins N, Mzolo S, Moodley T, Esterhuizen T, van Rooyen H. AIDS. 2009; 10;23:1851-7.

Rollins and colleagues set out to determine the acceptability and feasibility of universal HIV testing of 6-week-old infants attending immunization clinics to achieve early diagnosis of HIV and referral for HIV treatment and care services. The study design was an observational cohort within which routine HIV testing of infants was offered to all mothers bringing infants for immunizations at three clinics in KwaZulu Natal. Blood samples were collected by heel prick onto filter paper. Dried blood spots were tested for HIV antibodies and, if present, were tested for HIV DNA by PCR. Exit interviews were requested of all mothers irrespective of whether they had agreed to infant testing or not. Of 646 mothers bringing infants for immunizations, 584 (90.4%) agreed to HIV testing of their infant and 332 (56.8%) subsequently returned for results. Three hundred and thirty-two of 646 (51.4%) mothers and infants thereby had their HIV status confirmed or reaffirmed by the time the infant was 3 months of age. Overall, 247 of 584 (42.3%) infant dried blood spot samples had HIV antibodies indicating maternal HIV status. Of these, 54 (21.9%) samples were positive for HIV DNA by PCR. This equates to 9.2% (54/584) of all infants tested. The majority of mothers interviewed said they were comfortable with testing of their infant at immunization clinics and would recommend it to others. Screening of all infants at immunization clinics is acceptable and feasible as a means for early identification of HIV-infected infants and referral for antiretroviral therapy. 

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Editors’ note: With HIV infection widespread across KwaZulu-Natal, it is encouraging that 98% of the 90% of women who consented to have their baby tested reported having been tested themselves before. Linking HIV testing to immunisation visits during the first 3 months of life was convenient for mothers. High maternal antibody levels in infants at that age increased test sensitivity so that PCR testing could be used solely for those who had been exposed to HIV. Earlier infant diagnosis means earlier medical assessment and access to antiretroviral treatment. More work is needed to encourage mothers to return in a timely way for their child’s results (only mothers had the code to link up with the results) and to talk with other women about the advantages of knowing their child’s status (e.g. infant feeding choices to reduce post-natal HIV transmission, initiation of antiretroviral treatment if already infected, as per WHO guidelines for infants).

Routine offering of HIV testing to hospitalized paediatric patients at university teaching hospital, Lusaka, Zambia: acceptability and feasibility.

Kankasa C, Carter RJ, Briggs N, Bulterys M, Chama E, Cooper ER, Costa C, Spielman E, Katepa-Bwalya M, M’soka T, Ou CY, Abrams EJ. J Acquir Immune Defic Syndr. 2009;51:202-8.

The difficulties diagnosing infants and children with HIV infection have been cited as barriers to increasing the number of children receiving antiretroviral therapy worldwide. Kankasa and colleagues implemented routine HIV antibody counselling and testing for paediatric patients hospitalized at the University Teaching Hospital, a national reference centre, in Lusaka, Zambia. They also introduced HIV DNA polymerase chain reaction testing for early infant diagnosis. Caregivers/parents of children admitted to the hospital wards were routinely offered HIV counselling and testing for their children. HIV antibody positive (HIV+) children <18 months of age were tested with PCR for HIV DNA. From January 1, 2006, to June 30, 2007, among 15,670 children with unknown HIV status, 13,239 (84.5%) received counselling and 11,571 (87.4%) of those counselled were tested. Overall, 3373 (29.2%) of those tested were seropositive. Seropositivity was associated with younger age: 69.6% of those testing HIV antibody positive were <18 months of age. The proportion of counselled children who were tested increased each quarter from 76.0% in January to March 2006 to 88.2% in April to June 2007 (P < 0.001). From April 2006 to June 2007, 1276 polymerase chain reaction tests were done; 806 (63.2%) were positive. The rate of PCR positivity increased with age from 22% in children <6 weeks of age to 61% at 3-6 months and to 85% at 12-18 months (P < 0.001). Routine counselling and offers of antibody testing of paediatric inpatients can identify large numbers of HIV-seropositive children in high prevalence settings. The high rate of HIV infection in hospitalized infants and young children also underscores the urgent need for early infant diagnostic capacity in high prevalence settings.

Editors’ note: Globally, the number of children under 15 years of age who received antiretroviral treatment rose from 198,000 in 2007 to 275, 000 in 2008; however, a striking 62% of children in low- and middle-income countries who need antiretroviral treatment are not receiving it. Among the many barriers to overcome in the scale-up of paediatric HIV treatment to universal access, the major gatekeeper is identifying children with HIV infection. Before the study began in this Lusaka referral hospital, children were sent to adjacent voluntary testing and counselling centres for determination of serostatus. The uptake of paediatric testing among caregivers that were counselled on the wards increased over time to an overall 87%. The result was that 29% of the children tested were found to be HIV-antibody positive, 63% of whom were infected. There is no doubt that referral hospitals in high HIV prevalence countries can increase paediatric-testing uptake dramatically if HIV counselling and testing are offered routinely at the point of care .

When to start antiretroviral therapy in resource-limited settings.

Walensky RP, Wolf LL, Wood R, Fofana MO, Freedberg KA, Martinson NA, Paltiel AD, Anglaret X, Weinstein MC, Losina E; CEPAC (Cost-Effectiveness of Preventing AIDS Complications)-International Investigators. Ann Intern Med. 2009; 151:157-66.

The results of international clinical trials that are assessing when to initiate antiretroviral therapy will not be available for several years. The authors set out to inform HIV treatment decisions about the optimal CD4 threshold at which to initiate antiretroviral therapy in South Africa while awaiting the results of these trials by carrying out cost-effectiveness analysis of published data using a computer simulation model of HIV disease. The data were from randomized trials and observational cohorts in South Africa and the target population was HIV-infected patients in South Africa over a 5-year time horizon and over lifetime. The perspective was modified societal. The interventions considered were: no treatment, antiretroviral therapy initiated at a CD4 count less than 0.250 x 10(9) cells/L, and antiretroviral therapy initiated at a CD4 count less than 0.350 x 10(9) cells/L. The outcome measures were morbidity, mortality, life expectancy, medical costs, and cost-effectiveness. If 10% to 100% of HIV-infected patients are identified and linked to care, a CD4 count threshold for ART initiation of 0.350 x 10(9) cells/L would reduce severe opportunistic diseases by 22,000 to 221,000 and deaths by 25,000 to 253,000 during the next 5 years compared with ART initiation at 0.250 x 10(9) cells/L; cost increases would range from $142 million (10%) to $1.4 billion (100%). Either ART initiation strategy would increase long-term survival by at least 7.9 years, with a mean per-person life expectancy of 3.8 years with no ART and 12.5 years with an initiation threshold of 0.350 x 10(9) cells/L. Compared with an initiation threshold of 0.250 x 10(9) cells/L, a threshold of 0.350 x 10(9) cells/L has an incremental cost-effectiveness ratio of $1200 per year of life saved. Initiating antiretroviral therapy at a CD4 count less than 0.350 x 10(9) cells/L would remain cost-effective over the next 5 years even if the probability that the trial would demonstrate the superiority of earlier therapy is as low as 17%. This model does not consider the possible benefits of initiating antiretroviral therapy at a CD4 count greater than 0.350 x 10(9) cells/L or of reduced HIV transmission. Earlier initiation of antiretroviral therapy in South Africa will probably reduce morbidity and mortality, improve long-term survival, and be cost-effective. While awaiting trial results, treatment guidelines should be liberalized to allow initiation at CD4 counts less than 0.350 x 10(9) cells/L, earlier than is currently recommended.

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Editors’ note: This cost-effectiveness analysis of 3 options (no treatment and treatment initiation thresholds of 250 and 350 CD4 cell counts) using a computer simulation to model HIV disease helps answer a critical question in the South African national context. What at the clinical outcomes and costs over the short-term (5 years) of different decisions on treatment initiation, taking into account the chance that the trials currently studying antiretroviral initiation will demonstrate a clinical benefit of antiretroviral treatment initiation at the 350 cell count level? Although randomised controlled trials, rather than models, are the gold standard for developing policy, models can help inform policy. Inadequate treatment capacity may exacerbate inequities in treatment access and this should be carefully monitored regardless of CD4 count entry criteria. Changes in the WHO treatment guidelines are likely to be announced in the coming months, provoking many countries which have not done so to consider how to strengthen their strategies for scale-up to universal access.

Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study.

Guiguet M, Boué F, Cadranel J, Lang JM, Rosenthal E, Costagliola D; on behalf of the Clinical Epidemiology Group of the FHDH-ANRS CO4 cohort. Lancet Oncol. 2009 Oct 7. [Epub ahead of print]

The relative roles of immunodeficiency, HIV viral load, and combination antiretroviral therapy in the onset of individual cancers have rarely been examined. The authors examined the effect of these factors on the risk of specific cancers in patients infected with HIV-1. They investigated the incidence of both AIDS-defining cancers (Kaposi’s sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining cancers (Hodgkin’s lymphoma, lung cancer, liver cancer, and anal cancer) in 52 278 patients followed up in the French Hospital Database on HIV cohort during 1998-2006 (median follow-up 4.9 years, IQR 2.1-7.9; 255 353 person-years). They tested 78 models with different classifications of immunodeficiency, viral load, and combination antiretroviral therapy with Poisson regression. Current CD4 cell count was the most predictive risk factor for all malignancies apart from anal cancer. Compared with patients with CD4 count greater than 500 cells per muL, rate ratios ranged from 1.9 (95% CI 1.3-2.7) for CD4 counts 350-499 cells per muL to 25.2 (17.1-37.0) for counts less than 50 cells per muL for Kaposi’s sarcoma (p<0.0001), from 1.3 (0.9-2.0) to 14.8 (9.7-22.6) for non-Hodgkin lymphoma (p<0.0001), from 1.2 (0.7-2.2) to 5.4 (2.4-12.1) for Hodgkin’s lymphoma (p<0.0001), from 2.2 (1.3-3.6) to 8.5 (4.3-16.7) for lung cancer (p<0.0001), and from 2.0 (0.9-4.5) to 7.6 (2.7-20.8) for liver cancer (p<0.0001). For cervical cancer, they noted a strong effect of current CD4 (rate ratios 0.7 per log(2), 95% CI 0.6-0.8; p=0.0002). The risk of Kaposi’s sarcoma and non-Hodgkin lymphoma increased for current plasma HIV RNA greater than 100 000 copies per mL compared with patients with controlled viral load (RR 3.1, 95% CI 2.3-4.2, p<0.0001; and 2.9, 2.1-3.9, p<0.0001, respectively), whereas combination antiretroviral therapy was independently associated with a decreased incidence (0.3, 0.2-0.4, p<0.0001; and 0.8, 0.6-1.0, p=0.07, respectively). The rate ratios of cervical cancer for those receiving combination antiretroviral therapy was 0.5 (0.3-0.9; p=0.03). The risk of anal cancer increased with the time during which the CD4 count was less than 200 cells per muL (1.3 per year, 1.2-1.5; p=0.0001), and viral load was greater than 100 000 copies per mL (1.2 per year, 1.1-1.4, p=0.005). Combination antiretroviral therapy would be most beneficial if it restores or maintains CD4 count above 500 cells per muL, thereby indicating an earlier diagnosis of HIV infection and an earlier treatment initiation. Cancer-specific screening programmes need to be assessed in patients with HIV.

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Editors’ note: Patients with HIV have a higher risk than does the general population of both AIDS-defining and non-AIDS-defining cancers. However, since the introduction of antiretroviral treatment, the incidence of AIDS-defining cancers has decreased, whereas that of non-AIDS-defining cancers has increased. Both the size of this French cohort and its length of follow-up allowed investigation of seven specific cancers, finding that the risk of all of them increased with immunodeficiency. Among patients with Kaposi’s sarcoma, men who have sex with men are over-represented. Among patients with liver cancer and lung cancer, injecting drug users are over-represented. Antiretroviral treatment to keep CD4 counts above 500 cells combined with regular cervical-screening programmes for all HIV-positive women and early detection of anal cancer in men could help improve HIV-related cancer outcomes.

Macronutrient Supplementation for Malnourished HIV-Infected Adults: A Review of the Evidence in Resource-Adequate and Resource-Constrained Settings.

Koethe JR, Chi BH, Megazzini KM, Heimburger DC, Stringer JS. Clin Infect Dis. 2009; 49:787-98

Access to antiretroviral therapy for human immunodeficiency virus infection has expanded rapidly throughout sub-Saharan Africa, but malnutrition and food insecurity have emerged as major barriers to the success of antiretroviral therapy programs. Protein-calorie malnutrition (a common form of malnutrition in the region) hastens HIV disease progression, and food insecurity is a barrier to medication adherence. Analyses of patient outcomes have identified a low body mass index after the start of antiretroviral therapy as an independent predictor of early mortality, but the causes of a low body mass index are multifactorial (eg, normal anthropometric variation, chronic inadequate food intake, and/or wasting associated with HIV infection and other infectious diseases). Although there is much information on population-level humanitarian food assistance, few data exist to measure the effectiveness of macronutrient supplementation or to identify individuals most likely to benefit. In this report, Koethe and colleagues review the current evidence supporting macronutrient supplementation for HIV-infected adults and report on clinical trials in resource-adequate and resource-constrained settings, and highlight priority areas for future research.

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Editors’ note: This excellent review is a must-read for anyone wanting to learn in a nutshell what is known about the effects of malnutrition on HIV disease progression, the causes of increased mortality in malnourished people on antiretroviral treatment, and the advantages and disadvantages of the macronutrient supplements that are readily available now in low- and middle-income countries. The target intake should be 2100 kcal/day for adults increased by a additional 30% of patients with advanced HIV infection. Among the questions for future trials to address are the proportion of daily calories to supply, choice of supplement, duration of supplementation, acceptability and behaviour, logistics, and programme exit criteria.

Deworming helminth co-infected individuals for delaying HIV disease progression.

Walson JL, Herrin BR, John-Stewart G. Cochrane Database Syst Rev. 2009;3:CD006419.

The HIV-1 pandemic has disproportionately affected individuals in resource-constrained settings where other infectious diseases, such as helminth infections, also are highly prevalent. There are biologically plausible reasons for possible effects of helminth infection in HIV-1-infected individuals, and findings from multiple studies suggest that helminth infection may adversely affect HIV-1 progression. Since initial publication of this review (Walson 2007), additional data from randomized controlled trials has become available. Walson and colleagues therefore sought to evaluate all currently available evidence to determine if treatment of helminth infection in HIV-1 co-infected individuals impacts HIV-1 progression. They set out to determine if treating helminth infection in individuals with HIV-1 can reduce the progression of HIV-1 as determined by changes in CD4 count, viral load, or clinical disease progression. In this 2008 update, the authors searched online for published and unpublished studies in The Cochrane Library, MEDLINE, EMBASE, CENTRAL, and AIDSEARCH. They also searched databases listing conference abstracts, scanned reference lists of articles, and contacted authors of included studies. The authors searched for randomized controlled trials and quasi- randomized controlled trials that compared HIV-1 progression as measured by changes in CD4 count, viral load, or clinical disease progression in HIV-1 infected individuals receiving anti-helminthic therapy. Data regarding changes in CD4 count, HIV-1 RNA levels, and/or clinical staging after treatment of helminth co-infection were extracted from identified studies. Of 7,019 abstracts identified (6,384 from original searches plus 635 from updated searches), 17 abstracts were identified as meeting criteria for potential inclusion (15 from previous review plus an additional two randomized controlled trials). After restricting inclusion to randomized controlled trials, a total of three studies were eligible for inclusion in this updated review. All three trials showed individual beneficial effects of helminth eradication on markers of HIV-1 disease progression (HIV-1 RNA and/or CD4 counts). When data from these trials were pooled, the analysis demonstrated significant benefit of deworming on both plasma HIV-1 RNA and CD4 counts. To date, three randomized controlled trials have evaluated the effects of deworming on markers of HIV-1 disease progression in helminth and HIV-1 co-infected individuals. All trials demonstrate benefit in attenuating or reducing plasma viral load and/or increasing CD4 counts. When taken together, there is evidence of benefit for deworming HIV-1 co-infected adults. Given that these studies evaluated different helminth species and different interventions, further trials are warranted to evaluate species-specific effects and to document long-term clinical outcomes following deworming.

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Editors’ note: Between one-third and one-half of the global population is infected with at least one species of helminth (worms), with most infections found in low- and middle-income countries. Three randomised, controlled trials have now shown the short-term benefit on markers of HIV disease progression (CD4 counts, viral load) of treating helminth infection. These short term trials evaluated different interventions and different helminth infections (schistosomiasis, soil-transmitted helminths, and lymphatic filariasis) so it is premature to recommend empiric anti-helminthic therapy or routine helminth screening of HIV-infected adults. What is needed now are larger trials with longer follow-up to determine whether there are significant meaningful differences in clinical progression. In the meantime, helminth infection should be treated when it is found.