HIV This Week

Welcome to issue fifty-one of HIV This Week!  In this issue, we cover chronic disease (how HIV care approaches are bringing benefits to diabetes and hypertension care in Cambodia;high levels of obesity and hypertension pose challenges for preventing further cardiovascular risk with treatment scale-up in South Africa), sexual transmission and prevention (spectre on the horizon: increasing alcohol use in Africa), prevention of mother-to-child transmission (cell-associated HIV-1 shedding in breast milk due to mastitis; joint incentive for couples to remain HIV-free: preventing family illness and death), gender (what can you say about sex differences – not much if trials are not powered to be able to detect them), orphans and vulnerable children (need to spread the net wider in Kenya to benefit more disadvantaged children; mothers’ health and child survival are intricately linked in Tanzania), HIV testing (two-thirds of HIV transmission in Lusaka, Zambia occurs among co-habiting couples; African communities in London say what it would take for successful adaptation of the Kenya HIV testing model to their communities), basic science (opiates create brain fuddle – not what you need if you are living with HIV; preventing protease folding while avoiding resistance – new drug design?), treatment (in mathematical modelling, clinical monitoring in resource-limited settings proves its worth over CD4 count and viral load testing; treating anaemia, other infections, and malnutrition to prevent excessive mortality early in treatment), and sexual and reproductive health (what you didn’t want to know about semen quality).

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For full PDF access to this issue:HIV This Week Issue #51

Cate Hankins	Nicolai Lohse	Tania Lemay	Diane Addison
Chief Scientific Adviser	Research Officer	Research Consultant	Intern

Janssens B, Van Damme W, Raleigh B, Gupta J, Khem S, Soy Ty K, Vun M, Ford N, Zachariah R. Offering integrated care for HIV/AIDS, diabetes and hypertension within chronic disease clinics in Cambodia. Bull World Health Organ. 2007; 85(11):880-5.

In Cambodia, care for people living with HIV (prevalence 1.9%) is expanding, but care for people with type II diabetes (prevalence 5-10%), arterial hypertension, and other treatable chronic diseases remains very limited. Janssens and colleagues describe the experience and outcomes of offering integrated care for HIV, diabetes, and hypertension within the setting of chronic disease clinics. Chronic disease clinics were set up in the provincial referral hospitals of Siem Reap and Takeo, 2 provincial capitals in Cambodia. At 24 months of care, 87.7% of all HIV patients were alive and in active follow-up. For diabetes patients, this proportion was 71%. Of the HIV patients, 9.3% had died and 3% were lost to follow-up, while for diabetes this included 3 (0.1%) deaths and 28.9% lost to follow-up. Of all diabetes patients who stayed more than 3 months in the cohort, 90% were still in follow-up at 24 months. Over the first three years, the chronic disease clinics have demonstrated the feasibility of integrating care for HIV with non-communicable chronic diseases in Cambodia. Adherence support strategies proved to be complementary, resulting in good outcomes. Services were well accepted by patients, and this has had a positive effect on HIV -related stigma. This experience shows how care for HIV patients can act as an impetus to tackle other common chronic diseases.

Editors’ note: With antiretroviral therapy becoming more accessible in resource-constrained settings, HIV care is increasingly becoming chronic disease management. Integrating care for HIV, diabetes, and hypertension can have efficiency gains, improved patient outcomes, and reduction in HIV-related stigma. In many settings, HIV care has introduced adherence support functions into the health care system. These can be applied to other chronic diseases, often neglected despite their disease burden, that also require sustained adherence to medication and lifestyle changes.

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Bärnighausen T, Welz T, Hosegood V, Bätzing-Feigenbaum J, Tanser F, Herbst K, Hill C, Newell ML. Hiding in the shadows of the HIV epidemic: obesity and hypertension in a rural population with very high HIV prevalence in South Africa. J Hum Hypertens. 2008; 22(3):236-9..

Bärnighausen and colleagues conducted a large population-based survey of body mass and blood pressure nested within an HIV survey in rural KwaZulu-Natal, South Africa, to measure the prevalence of obesity and hypertension in a community with very high HIV prevalence and to investigate the effect of HIV on body mass and blood pressure in a general population in rural Africa before antiretroviral treatment was widely available. Crude prevalence of overweight, obesity, stage-I and stage-II hypertension was 58% (95% confidence interval (CI) 56–60%), 32% (95% CI 30–33%), 24% (95% CI 22–26%) and 9% (95% CI 8–10%), respectively. Controlling for age, sex, education, household wealth, marital status and rural vs urban residence in multiple regression (after multiple imputation of missing values), HIV infection reduced body mass index by 1.9 units (Po0.001) and––when additionally controlling for body mass––systolic blood pressure by 3.0mmHg (P¼0.005).

Editors’ note: Despite an HIV prevalence of 35% in this 2003-2004 population-based survey, more than half of people were overweight, a third were obese and a third had high blood pressure. HIV had an effect on body mass index equivalent to a 5 kg. weight reduction and was a significant predictor of lower systolic blood pressure – findings that will likely be reversed as antiretroviral treatment is scaled up. This highlights the relevance of integrated chronic disease management to increase antihypertensive treatment coverage and promote lifestyle modification for HIV patients starting on antiretroviral treatment, as well as for the general population.

Fisher JC, Bang H, Kapiga SH. The association between HIV infection and alcohol use: a systematic review and meta-analysis of African studies. Sex Transm Dis. 2007; 34(11):856-63.

Fisher and colleagues amied to summarize the association between alcohol use and human immunodeficiency virus (HIV) infection based on studies conducted in Africa. EMBASE and PubMed were searched for African studies that related alcohol use to HIV infection. Meta-analyses were conducted to obtain pooled univariate and multivariate relative risk estimates. Subgroup analyses were performed for studies having different sample types: males or females and population-based or high-risk, and ones that differentiated between problem and asymptomatic drinkers. Alcohol drinkers were more apt to be HIV+ than nondrinkers. The pooled unadjusted odds ratio (OR) from 20 studies was 1.70 (95% confidence interval, CI = 1.45-1.99). Results from 11 studies that adjusted for other risk factors produced a pooled risk estimate of 1.57 (95% CI = 1.42-1.72). Males and females had similar risk estimates, while studies involving high-risk samples tended to report larger pooled odds ratios than studies of the general population. When compared with nondrinkers, the pooled estimates of HIV risk were 1.57 (95% CI = 1.33-1.86) for non-problem drinkers versus 2.04 (95% CI = 1.61-2.58 ) for problem drinkers, a statistically significant difference (z = 2.08, P <0.04). Alcohol use was associated with HIV infection in Africa and alcohol-related interventions might help reduce further expansion of the epidemic.

Editors’ note: This systematic review and meta-analysis found alcohol drinkers to have a 57% increased risk of HIV infection after controlling for potential confounders, with the heaviest and symptomatic drinkers at greatest risk, suggesting a dose-response relationship. Beyond its direct immune suppressive effects, alcohol increases risk indirectly through other factors such as high-risk behaviour, gender violence, and presence of other sexually transmitted infections. With low alcohol content traditional home brews increasingly being replaced by high alcohol content commercial brews, alcohol consumption in Africa is on the rise. Prevention programming with a focus on responsible drinking and safer sex could create a more favourable social context in small bars and other informal alcohol serving establishments to avert alcohol-induced amplification of HIV transmission.

Kantarci S, Koulinska IN, Aboud S, Fawzi WW, Villamor E. Subclinical Mastitis, Cell-Associated HIV-1 Shedding in Breast Milk, and Breast-Feeding Transmission of HIV-1. J Acquir Immune Defic Syndr. 2007; 46(5):651-654.

Mastitis has been identified as a risk factor for mother-to-child transmission of HIV-1 through breast-feeding. It is unclear whether this association is mediated by increased cell-free virus versus cell-associated virus HIV shedding in breast milk. Kantarci and colleagues examined the risk of mother-to-child transmission associated with subclinical mastitis and the relation between mastitis and cell-free virus or cell-associated virus shedding in breast milk. Fifty-nine women who transmitted HIV through breast-feeding (cases) were individually matched to 59 non-transmitting controls nested in a cohort from Tanzania. For each case, the authors selected a milk specimen obtained before the infant’s first positive test to quantify sodium and potassium and measure cell-free virus and cell-associated virus concentrations. Controls were matched on the child’s age at the time of sample collection. Women with a breast milk sodium/potassium ratio suggestive of mastitis (>1.0) had an 11-fold greater odds of transmission (95% confidence interval [CI]: 1.2 to 98.1), compared to women with a sodium/potassium ratio </=0.6, after adjusting for maternal CD4 cell count and vitamin A supplementation. Although mastitis was positively related to both cell-free virus and cell-associated virus shedding in breast milk, only the association with the latter was strong and statistically significant. In conclusion, increased cell-associated HIV-1 shedding in breast milk could mediate the association between mastitis and mother-to-child transmission.

Editors’ note: Simpler methods to diagnose sub-clinical mastitis, studies to determine when it is safe to resume breast-feeding from the affected breast, and the results of current trials underway assessing the prevention efficacy of antiretroviral treatment provided to HIV-positive lactating women and/or their breastfeeding infants are needed for informed policy guidance.

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Heymann SJ, Clark S, Brewer TF. Moving from preventing HIV/AIDS in its infancy to preventing family illness and death (PFID). IntJ Infect Dis. 2008; 12(2):117-9.

In April 2007, UNAIDS released Securing the future-advocating for children, a call for the global community to recognize that “children still remain largely absent from national and international political responses to the AIDS pandemic”. Most efforts to date to protect children from HIV have focused on prevention of mother-to-child transmission programs. Though expanding prevention of mother-to-child transmission programs, particularly in sub-Saharan Africa, are crucial, even widespread prevention of mother-to-child transmission programs would still be grossly inadequate for achieving the goal of protecting children from HIV. The global community needs to fundamentally reframe its approach to HIV prevention to fully address the health of families; otherwise the future for at-risk children is likely to remain bleak. After identifying challenges with current approaches, Heymann and colleagues review recent research that provides insights into ways prevention programs may be adapted to better protect families and children from the devastating consequences of HIV. Only by protecting families from HIV will we be able to achieve the goal of an HIV-free generation.

Editors’ note: HIV prevention among partners is key to preventing children becoming infected or being orphaned due to HIV. Couples have a joint incentive to remain HIV-free, to identify HIV infection in either partner early to prevent onward transmission and access treatment, and to make fertility plans together.

Hoffman RM, Umeh OC, Garris C, Givens N, Currier JS. Evaluation of Sex Differences of Fosamprenavir (With and Without Ritonavir) in HIV-Infected Men and Women. HIV Clin Trials. 2007; 8(6):371-80.

Recent studies focusing on HIV-1-infected women have suggested the existence of sex-related differences in natural history, antiretroviral pharmacokinetics, efficacy, and tolerability. This article analyzes three pivotal trials of the protease inhibitor (PI) fosamprenavir (FPV) with a view to providing a better understanding of potential sex differences in efficacy and safety. A post hoc, descriptive analysis was performed on data from 700 subjects (26% women) in three trials of FPV to evaluate sex differences with regard to efficacy, rates of discontinuation, and treatment-related adverse events. No major sex differences were found. Men and women had similarly good antiviral responses, with greater than 60% of treatment-naïve subjects achieving virologic suppression (<400 copies/mL) at 48 weeks. PI-experienced women in CONTEXT receiving once-daily FPV/r experienced the highest rates of discontinuations due to virologic failure (29% in women vs. 8% in men). Women generally had slightly lower rates of liver enzyme elevations and fewer abnormalities of total cholesterol and triglycerides. In conclusion, the absence of major sex differences provides reassurance, but the small number of women in these trials limited the ability to draw conclusions. Future trials should be specifically powered to detect sex differences in safety and efficacy.

Editors’ note: This retrospective analysis attempts to pull together data from three trials to overcome the low numbers of participating women. Finding no sex-based differences does not mean that these do not exist when studies are not designed to be able to detect them. The December 2007 Geneva consultation ‘Making HIV trials work for women and adolescent girls’ concluded that for clinical trials to include a scientifically meaningful number of women, a new norm in clinical trial conduct would need to be fostered.

Mishra V, Arnold F, Otieno F, Cross A, Hong R. Education and nutritional status of orphans and children of HIV-infected parents in Kenya. AIDS Educ Prev. 2007;19(5):383-95.

Mishra and colleagues examined whether orphaned and fostered children and children of HIV-infected parents are disadvantaged in schooling, nutrition, and health care. The authors analyzed data on 2,756 children aged 0-4 years and 4,172 children aged 6-14 years included in the 2003 Kenya Demographic and Health Survey, with linked anonymous HIV testing, using multivariate logistic regression. Results indicate that orphans, fostered children, and children of HIV-infected parents are significantly less likely to attend school than non-orphaned/non-fostered children of HIV-negative parents. Children of HIV-infected parents are more likely to be underweight and wasted, and less likely to receive medical care for ARI and diarrhoea. Children of HIV-negative single mothers are also disadvantaged on most indicators. The findings highlight the need to expand child welfare programs to include not only orphans but also fostered children, children of single mothers, and children of HIV-infected parents, who tend to be equally, if not more, disadvantaged.

Editors’ note: Recognition of the vulnerability of children who have not been orphaned by AIDS led to the acronym ‘OVC’ (orphans and vulnerable children) which casts the net more widely. Child welfare programmes that include all disadvantaged children are more likely to mitigate the effects of the epidemic on children while preventing HIV from getting a toehold in the next generation.

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Chatterjee A, Bosch RJ, Hunter DJ, Fataki MR, Msamanga GI, Fawzi WW. Maternal disease stage and child undernutrition in relation to mortality among children born to HIV-infected women in Tanzania. J Acquir Immune Defic Syndr. 2007; 46(5):599-606.

Chatterjee and colleagues examine whether maternal HIV disease stage during pregnancy and child malnutrition are associated with child mortality in a prospective cohort study in Tanzania. Indicators of disease stage were assessed for 939 HIV-infected women during pregnancy and at delivery, and children’s anthropometric status was obtained at scheduled monthly clinic visits after delivery. Children were followed up for survival status until 24 months after birth. Advanced maternal HIV disease during pregnancy (CD4 count <350 vs. >or=350 cells/mm) was associated with increased risk of child mortality through 24 months of age (hazard ratio [HR] = 1.74, 95% confidence interval [CI]: 1.32 to 2.30). CD4 count <350 cells/mm was also associated with an increased risk of death among children who remained HIV-negative during follow-up (HR = 2.00, 95% CI: 1.36 to 2.94). Low maternal haemoglobin concentration and child undernutrition were related to an increased risk of mortality in this cohort of children. The authors conclude that low maternal CD4 cell count during pregnancy is related to increased risk of mortality in children born to HIV-infected women. Care and treatment for HIV disease, including highly active antiretroviral therapy to pregnant women, could improve child survival. Prevention and treatment of undernutrition in children remain critical interventions in settings with high HIV prevalence.

Editors’ note: The association between mothers’ advanced disease stage and child mortality is complex. Such mothers may transit a more virulent virus strain, may transmit other infections, may not provide as strong passive immunity to their offspring (across the placenta during pregnancy and in breast milk during breastfeeding), and may have reduced parenting capacity due to anaemia, fatigue, and HIV-related disease. To increase child survival in high HIV prevalence areas, integration of maternal and child health programmes with antiretroviral treatment programmes can help prevent and treat childhood malnutrition, while addressing the maternal anaemia and opportunistic infections that can undermine parenting capacity.

Chomba E, Allen S, Kanweka W, Tichacek A, Cox G, Shutes E, Zulu I, Kancheya N, Sinkala M, Stephenson R, Haworth A. Evolution of Couples’ Voluntary Counseling and Testing for HIV in Lusaka, Zambia. J Acquir Immune Defic Syndr 2008; 47(1):108-15.

Chomba and colleagues describe promotional strategies for couples’ voluntary HIV counselling and testing and demographic risk factors for couples in Lusaka, Zambia, where an estimated two thirds of new infections occur in cohabiting couples. Couples’ voluntary HIV counselling and testing attendance as a function of promotional strategies is described over a 6-year period. Cross-sectional analyses of risk factors associated with HIV in men, women, and couples are presented. Community workers recruited from couples seeking voluntary HIV counselling and testing promoted testing in their communities. Attendance dropped when community worker outreach ended, despite continued mass media advertisements. In Lusaka, 51% of 8500 cohabiting couples who sought HIV testing were concordant negative for HIV and 26% concordant positive; 23% of couples were serodiscordant (that is, had 1 HIV-positive partner/1 HIV-negative partner), with 11% HIV-positive man/HIV-negative woman and 12% HIV-negative man/HIV-positive woman. HIV infection was associated with men’s age 30 to 39, women’s age 25 to 34, duration of union <3 years, and number of children <2. Even among couples with only 1-2 or no risk factors, HIV prevalence was 45% and 29%, respectively. Many married African adult couples do not have high-risk profiles, nor do they realize that one of the partners may have HIV. Active and sustained promotion is needed to encourage all couples to be jointly tested and counselled.

Editors’ note: This study highlights the importance of knowing your epidemic and tailoring effective responses to it. In mature HIV epidemics such as this one, as much as two-thirds of all HIV transmission is occurring within cohabiting couples. Serodiscordant couples have an HIV prevalence of 50% in their marital bed of which they may be unaware. Community mobilisation to create new social norms around knowledge of serostatus and the advantages of joint testing can provide couples with the opportunity to learn how they can prevent HIV from entering, or being transmitted within, their couple, while linking those already infected to treatment and support services. This study focused on couples seeking testing but home-based testing outreach in the community can achieve very high uptake with few negative social consequences if communities are engaged in the design, conduct, and evaluation of such programmes.

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Prost A, Sseruma WS, Fakoya I, Arthur G, Taegtmeyer M, Njeri A, Fakoya A, Imrie J. HIV voluntary counselling and testing for African communities in London: learning from experiences in Kenya. Sex Transm Infect. 2007;83:547-51.

Prost and colleagues explore the feasibility and acceptability of translating a successful voluntary counselling and testing service model from Kenya to African communities in London. The authors conducted a qualitative study with focus group discussions and a structured workshop with key informants. Five focus group discussions were conducted in London with 42 participants from 14 African countries between August 2006 and January 2007. A workshop was held with 28 key informants. Transcripts from the group discussions and workshop were analysed for recurrent themes. Participants indicated that a community-based HIV voluntary counselling and testing service would be acceptable to African communities in London, but also identified barriers to uptake: HIV-related stigma, concerns about confidentiality, and doubts about the ability of community-based services to maintain professional standards of care. Workshop participants highlighted three key requirements to ensure feasibility: (a) efficient referrals to sexual health services for the newly diagnosed; (b) a locally appropriate testing algorithm and quality assurance scheme; (c) a training programme for voluntary counselling and testing counsellors. In conclusion, offering a community-based voluntary counselling and testing with rapid HIV tests appears feasible within a UK context and acceptable to African communities in London, provided that clients’ confidentiality is ensured and appropriate support is given to the newly diagnosed. However, the persistence of concerns related to HIV-related stigma among African communities suggests that routine opt-out testing in healthcare settings may also constitute an effective approach to reducing the proportion of late diagnoses in this group. HIV service models and programmes from Africa constitute a valuable knowledge base for innovative interventions in other settings, including developed countries.

Editors’ note: Provider-initiated testing and counselling can reduce the proportion of late diagnoses among African communities in cities such as London but it does not address the issue of HIV-related stigma. Research such as this, working with communities to identify barriers and facilitators of feasibility and acceptance, is key to ensuring that community-based testing increases knowledge of serostatus in a supportive environment.

Hauser KF, El-Hage N, Buch S, Nath A, Tyor WR, Bruce-Keller AJ, Knapp PE. Impact of opiate-HIV-1 interactions on neurotoxic signaling. J Neuroimmune Pharmacol. 2006; 1(1):98-105.

Opiate drug abuse exacerbates the pathogenesis of human immunodeficiency virus-1 (HIV-1) in the central nervous system through direct actions on glia and neurons. Opiate abuse causes widespread disruption of astroglial and microglial function, and significant increases in astroglial-derived proinflammatory cytokines and chemokines, which likely contributes to neuronal dysfunction, death, and HIV encephalitis. Neurons are also directly affected by opiate-HIV-1 interactions. HIV-1 and the viral proteins gp120 and Tat activate multiple caspase-dependent and caspase-independent proapoptotic pathways in neurons involving phosphatidylinositol 3-kinase (PI3 kinase)/Akt, as well as p38, c-Jun N-terminal kinase (JNK) and/or other mitogen-activated protein kinases (MAPKs). Opiates appear to decrease the threshold for HIV-1-mediated neurotoxicity by sending convergent signals that exacerbate proapoptotic events induced by viral and cellular toxic products. The synergistic proinflammatory and neurotoxic effects of opiate drugs on glia and neurons are largely mediated through mu opioid receptors, which are expressed by subpopulations of astroglia, microglia, and neurons. Opiate abuse intrinsically modifies the host response to HIV-1. Identification of how this occurs is providing considerable insight toward understanding the mechanisms underlying HIV-1-associated dementia.

Editors’ note: HIV can cause neurotoxicity leading to symptoms and signs of dementia in some individuals and not others. Substances may exist that can counter this HIV-induced neurotoxicity but opiates are certainly not among them. Opiates appear to confuse neural communications and increase inflammation, undermining natural defences.

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Broglia R, Levy Y, Tiana G. HIV-1 protease folding and the design of drugs which do not create resistance. Curr Opin Struct Biol. 2008; 18(1):60-6.

Human immunodeficiency virus type 1 (HIV-1) protease plays an essential role in the life cycle of the virus. Consequently, its inhibition can control acquired immunodeficiency syndrome. Any pharmacological treatment targeting the active site of the protease is known to generate escape mutants. On the other hand, if a drug targets a site crucial for the correct folding of the protease, mutations affecting this region would denaturate the protein and thus will not be expressed. Broglia and colleagues review the progress in our understanding of the folding of the protease, which has been instrumental in the design of a (non-conventional) folding inhibitor. The transferability of these results to other proteins testify to the universality of the folding-inhibition scenario for the design of leads of drugs which are unlikely to generate resistance.

Editors’ note: A drug that could incapacitate HIV’s protease by inhibiting it from folding into an action position, without producing an escape mutant, would be an important step forward.

Phillips AN, Pillay D, Miners AH, Bennett DE, Gilks CF, Lundgren JD. Outcomes from monitoring of patients on antiretroviral therapy in resource-limited settings with viral load, CD4 cell count, or clinical observation alone: a computer simulation model. Lancet. 2008 ;371(9622):1443-51.

In lower-income countries, the World Health Organization (WHO) recommends a population-based approach to antiretroviral treatment with standardized regimens and clinical decision making based on clinical status and, where available CD4 cell count, rather than viral load. Phillips and colleagues aimed to study the potential consequences of such monitoring strategies, especially in terms of survival and resistance development. A validated computer simulation model of HIV infection and the effect of antiretroviral therapy was used to compare survival, use of second-line regimens, and development of resistance that result from different strategies-based on viral load, CD4 cell count, or clinical observation alone-for determining when to switch people starting antiretroviral treatment with the WHO-recommended first-line regimen of stavudine, lamivudine, and nevirapine to second-line antiretroviral treatment. Over 5 years, the predicted proportion of potential life-years survived was 83% with viral load monitoring (switch when viral load >500 copies per mL), 82% with CD4 cell count monitoring (switch at 50% drop from peak), and 82% with clinical monitoring (switch when two new WHO stage 3 events or a WHO stage 4 event occur). Corresponding values over 20 years were 67%, 64%, and 64%. Findings were robust to variations in model specification in extensive univariable and multivariable sensitivity analyses. Although survival was slightly longer with viral load monitoring, this strategy was not the most cost effective. For patients on the first-line regimen of stavudine, lamivudine, and nevirapine the benefits of viral load or CD4 cell count monitoring over clinical monitoring alone are modest. Development of cheap and robust versions of these assays is important, but widening access to antiretrovirals-with or without laboratory monitoring-is currently the highest priority.

Editors’ note: This mathematical modelling demonstrates that lack of access to laboratory monitoring with CD4 counts or viral load should not hinder antiretroviral treatment scale-up. Relying on clinical monitoring alone does not have marked detrimental effects on patient survival or development of resistance. However, precise definitions of clinical failure and specific training materials are needed to improve detection and diagnosis of the conditions that suggest that a switch to second-line treatment is necessary.

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Marazzi MC, Liotta G, Germano P, Guidotti G, Altan AD, Ceffa S, Lio MM, Nielsen-Saines K, Palombi L. Excessive Early Mortality in the First Year of Treatment in HIV Type 1-Infected Patients Initiating Antiretroviral Therapy in Resource-Limited Settings. AIDS Res Hum Retroviruses. 2008 Mar 26 [Epub ahead of print].

The response to treatment and risk factors for early mortality following initiation of combination antiretroviral therapy in a cohort of African patients are described in a retrospective cohort design. Medical history, laboratory parameters, and mortality data were reviewed for patients initiating antiretroviral therapy in 12 clinical centres in Mozambique , Tanzania, and Malawi. Among 3456 HIV-1-infected patients who received antiretroviral therapy for more than 6 months, at baseline 72% had WHO clinical stages 3/4, 7% had a viral load <400 copies/ml, and 38% had a CD4 cell count >200/mm3. One year later, 78% had undetectable virus loads and 79% had CD4 cell counts >200 cells/mm3. In the first year of antiretroviral therapy 260 deaths occurred (97 per 1000 person/years) with mortality peaking in the first 3 months. The highest mortality was observed in patients with low body mass index, low haemoglobin levels, and CD4 values <200 cells/mm3 at baseline. Mortality rates following initiation of antiretroviral therapy are higher in patients in resource-limited areas, particularly in the first 90 days following treatment initiation. Antiretroviral therapy initiated at higher CD4 cell count levels, especially among malnourished and/or anaemic patients, will carry significant public health impact.

Editors’ note: Mortality in the initial months of starting antiretroviral treatment is higher in resource-limited than in high-income settings, even when controlling for CD4 count at treatment initiation. This is likely due to higher prevalence of co-infections such as malaria, low haemoglobin (anaemia), and body mass indices below 18 (malnutrition). Mortality could be reduced by treating anaemia, malnutrition, and co-infections, and by starting antiretroviral treatment earlier in people with these co-morbidities.

van Leeuwen E, Wit FW, Repping S, Eeftinck Schattenkerk JK, Reiss P, van der Veen F, Prins JM. Effects of antiretroviral therapy on semen quality. AIDS. 2008; 22(5):637-42.

Van Leeuwen and colleagues aimed to evaluate the effect of combination antiretroviral therapy on semen quality in a longitudinal cohort study from the HIV outpatient clinic of the Academic Medical Centre in Amsterdam, the Netherlands. A cohort of 34 male patients with different estimated duration of HIV-1 infection, who were about to start various combinations of combination antiretroviral therapy, were included. Blood and semen were analyzed before the start of combination antiretroviral therapy and 4, 12, 24, 36 and 48 weeks thereafter. The authors examined the effect of combination antiretroviral therapy on semen parameters by a repeated measurements procedure using a mixed-effects model. The median period of follow up was 48 weeks (interquartile range 33-52 weeks). Five patients used thymidine analogue-containing combination antiretroviral therapy, 23 used tenofovir-based combination antiretroviral therapy, six used other regimens. At all timepoints the percentage of progressively motile spermatozoa was low according to WHO criteria, and it decreased significantly from 28 to 17% during follow-up (P = 0.02). All other semen parameters were in the normal range and remained stable. In conclusion, combination antiretroviral therapy negatively affected the percentage of progressively motile spermatozoa. Whether this reduced motility affects the chances of fathering a child or leads to an increased need for artificial reproductive techniques is at present unknown.

Editors’ note: This longitudinal study was short in duration but had the advantage that each man starting on antiretroviral treatment served as his own before/after control. All semen parameters remained normal with the exception of reduced spermatozoa motility. This may be mediated by mitochondrial dysfunction causing mitochondrial depletion or by some other mechanism linked to one or more drug classes. Whether this effect persists over time and whether it has an effect on fertility remain unknown and deserve more study.