HIV This Week

Eaton LA, Kalichman S. Risk compensation in HIV prevention: implications for vaccines, microbicides, and other biomedical HIV prevention technologies. Curr HIV/AIDS Rep. 2007;4:165-72.

Photo credit: unaids/fsanchez

Studies investigating the effects of biologic HIV prevention technologies have been reported with promising results for slowing the spread of the disease. Although they can reduce the rate of HIV transmission at varying levels of efficaciousness, it is vital to anticipate their impact on subsequent sexual behaviours. Risk homeostasis theory posits that decreases in perceived risk, which will occur with access to HIV prevention technologies, will correspond with increases in risk-taking behaviour. Here Eaton and colleagues review the literature on risk compensation in response to HIV vaccines, topical microbicides, antiretroviral medications, and male circumcision. Behavioural risk compensation is evident in response to prevention technologies that are used in advance of HIV exposure and at minimal personal cost. The authors conclude that behavioural risk compensation should be addressed by implementing adjunct behavioural risk-reduction interventions to avoid negating the preventive benefits of biomedical HIV prevention technologies.

Reducing viral load, highly active antiretroviral therapy has the potential to limit onwards transmission of HIV-1 and thus help contain epidemic spread. However, increases in risk behaviour and resurgent epidemics have been widely reported post-highly active antiretroviral therapy. The aim of this study was to quantify the impact that highly active antiretroviral therapy had on the epidemic. Bezemer and colleagues focus on the HIV-1 epidemic among men who have sex with men in the Netherlands, which has been well documented over the past 20 years within several long-standing national surveillance programs. The authors used a mathematical model including highly active antiretroviral therapy use and estimated the changes in risk behaviour and diagnosis rate needed to explain annual data on HIV and AIDS diagnoses. They show that the reproduction number R(t), a measure of the state of the epidemic, declined early on from initial values above two and was maintained below one from 1985 to 2000. Since 1996, when highly active antiretroviral therapy became widely used, risk behaviour rate has increased 66%, resulting in an increase of R(t) to 1.04 in the latest period 2000-2004 (95% confidence interval 0.98-1.09) near or just above the threshold for a self-sustaining epidemic. Hypothetical scenario analysis shows that the epidemiological benefits of highly active antiretroviral therapy and earlier diagnosis on incidence have been entirely offset by increases in the risk behaviour rate. This study provides the first detailed quantitative analysis of the HIV epidemic in a well-defined population and find a resurgent epidemic in the era of highly active antiretroviral therapy, most likely predominantly caused by increasing sexual risk behaviour.

Ryan M, Griffin S, Chitah B, Walker AS, Mulenga V, Kalolo D, Hawkins N, Merry C, Barry MG, Chintu C, Sculpher MJ, Gibb DM. The cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia. AIDS. 2008;22(6):749-57.

Ryan and colleagues aimed to assess the cost-effectiveness of cotrimoxazole prophylaxis in HIV-infected children in Zambia, as implementation at the local health centre level has yet to be undertaken in many resource-limited countries despite recommendations in recent updated World Health Organization (WHO) guidelines. A probabilistic decision analytical model of HIV progression in children based on the CD4 cell percentage (CD4%) was populated with data from the placebo-controlled Children with HIV Antibiotic Prophylaxis trial that had reported a 43% reduction in mortality with cotrimoxazole prophylaxis in HIV-infected children aged 1-14 years. Unit costs (US$ in 2006) were measured at University Teaching Hospital, Lusaka. Cost-effectiveness, expressed as cost per life-year saved; cost per quality adjusted life-year saved; and cost per disability adjusted life-year averted, was calculated across a number of different scenarios at tertiary and primary healthcare centres. Cotrimoxazole prophylaxis was associated with incremental cost-effectiveness ratios of US$72 per life-year saved, US$94 per quality adjusted life-year saved, and US$53 per disability adjusted life-year averted, i.e. substantially less than a cost-effectiveness threshold of US$1019 per outcome (gross domestic product per capita, Zambia 2006). Incremental cost-effectiveness ratios of US$5 or less per outcome demonstrate that cotrimoxazole prophylaxis is even more cost-effective at the local healthcare level. The intervention remained cost-effective in all sensitivity analyses including routine haematological and CD4% monitoring, varying starting age, AIDS status, cotrimoxazole formulation, efficacy duration, and discount rates. Cotrimoxazole prophylaxis in HIV-infected children is an inexpensive low technology intervention that is highly cost-effective in Zambia, strongly supporting the adoption of WHO guidelines into essential healthcare packages in low-income countries.

Editors´note: Along with other factors, cost-effectiveness analyses can inform decision-making on competing priorities. In this case, highly cost-effective cotrimoxazole in children with HIV infection is life-saving, simple, well–tolerated and inexpensive. It is a key element of pre-antiretroviral treatment care and part of the HIV chronic care package. The gap between World Health Organisation guidance and actual practice at the country level in sub-Saharan Africa needs to close rapidly for all children with HIV infection.

Dandona L, Kumar SG, Ramesh YK, Rao MC, Marseille E, Kahn JG, Dandona R. BMC Health Serv Res. 2008;8:26. Outputs, cost and efficiency of public sector centres for prevention of mother to child transmission of HIV in Andhra Pradesh, India.

Prevention of mother to child transmission is an important part of the effort to control HIV. PMTCT services are mostly provided at public sector government hospitals in India. Systematic data on the cost and efficiency of providing prevention of mother-to-child transmission services in India are not available readily for further planning. Cost and output data were collected at 16 sampled prevention of mother to child transmission centres in the south Indian state of Andhra Pradesh using standardized methods. The services provided were analysed, and the relation of unit cost of services with scale was assessed. In the 2005-2006 fiscal year, 125,073 pregnant women received prevention of mother to child transmission services at the 16 centres (range 2,939 to 20,896, median 5,679). The overall HIV positive rate among those tested was 1.67%. Of the total economic cost, the major components were personnel (47.3%) and recurrent goods (31.7%). For the 16 prevention of mother-to-child transmission centres, the average economic cost per post-HIV-test counselled pregnant woman was Indian Rupees (INR) 98.9 (US$ 2.23), ranging 2.7-fold from INR 71.4 (US$ 1.61) to INR 189.9 (US$ 4.29). The economic cost per mother-neonate pair who received nevirapine had a higher variation, ranging 41-fold for the 16 centres from INR 4,354 (US$ 98 ) to INR 179,175 (US$ 4,047), average INR 10,210 (US$ 231), with very high unit cost at some centres where HIV prevalence among pregnant women and the total volume of services were both low. Scale had a significant inverse relation with both of the unit costs, per post-HIV-test counselled pregnant woman and per mother-neonate pair who received nevirapine. In addition, HIV prevalence among pregnant women had a significant inverse relation with unit cost per mother-neonate pair who received nevirapine. Although the variation between prevention of mother-to-child transmission centres for unit cost per post-HIV-test counselled pregnant woman was modest that per mother-neonate pair receiving nevirapine was over 40-fold. The extremely high unit cost for each mother-neonate pair receiving nevirapine at some centres suggests that the new approach of combining prevention of mother to child transmission services with voluntary counselling and testing services that has recently been started in India could potentially offer better efficiency.

Editors’ note: An inverse relationship between unit cost and scale makes common sense. The piece that is missing in the equation is how many pregnancies in these 16 prevention of mother-to-child transmission centres were unplanned and unwanted. Integrating these services with voluntary counselling and testing services makes more than economical sense if fertility counselling is offered to all men and women testing HIV-positive.

Keiser O, Orrell C, Egger M, Wood R, Brinkhof MW, Furrer H, van Cutsem G, Ledergerber B, Boulle A; for the Swiss HIV Cohort Study (SHCS) and the International Epidemiologic Databases to Evaluate AIDS in Southern Africa (IeDEA-SA). Public-Health and Individual Approaches to Antiretroviral Therapy: Township South Africa and Switzerland Compared. PLoS Med. 2008;5(7):e148.

The provision of highly active antiretroviral therapy in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. Keiser and colleagues compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting highly active antiretroviral therapy in South Africa and Switzerland. The authors analysed data from the Swiss HIV Cohort Study and two highly active antiretroviral therapy programmes in townships of Cape Town, South Africa. They included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded injecting drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4(+) T cell counts were 80 cells/mul in South Africa and 204 cells/mul in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%-97%) in South Africa and 96% (94%-97%) in Switzerland, and 26% (22%-29%) and 27% (24%-31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of highly active antiretroviral therapy: adjusted hazard ratios were 5.90 (95% CI 1.81-19.2) during months 1-3 and 1.77 (0.90-3.50) during months 4-24. Compared to the highly individualised approach in Switzerland, programmatic highly active antiretroviral therapy in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to highly active antiretroviral therapy and improve the prognosis of patients who start highly active antiretroviral therapy with advanced disease.

Editors´note: It is reassuring that the public health treatment approach in South Africa is as effective virologically as is the individualized approach of Switzerland: 96% of patients in both South Africa and Switzerland suppressed viral load to less than 500 copies/ml within a year. Although similar percentages developed viral rebound within two years, there were differences in mortality primarily due to the much lower CD4 count in South Africans (median 80) compared to Swiss (median of 204) at baseline. Know your status campaigns that provide social support for HIV testing and counselling would permit earlier initiation of treatment and reduce early mortality in South Africans on treatment. On the Swiss side, Switzerland could well consider simplifying its 36 first-line regimens.

Youngpairoj AS, Masciotra S, Garrido C, Zahonero N, de Mendoza C, García-Lerma JG. HIV-1 drug resistance genotyping from dried blood spots stored for 1 year at 4 degrees Celsius. J Antimicrob Chemother. 2008 Mar 15 [Epub ahead of print]

Dried blood spots are an attractive alternative to plasma for HIV-1 drug resistance testing in resource-limited settings. Youngpairoj and colleagues recently showed that HIV-1 can be efficiently genotyped from dried blood spots stored at -20 degrees C for prolonged periods (0.5-4 years). Here, the authors evaluated the efficiency of genotyping from dried blood spots stored at 4 degrees C for 1 year. A total of 40 dried blood spots were prepared from residual diagnostic specimens collected from HIV subtype B-infected persons and were stored with desiccant at 4 degrees C. Total nucleic acids were extracted after 1 year using a modification of the Nuclisens assay. Resistance testing was performed using the ViroSeq HIV-1 assay and an in-house nested Reverse Transciptase PCR method validated for HIV-1 subtype B that amplifies a smaller (1 kb) pol fragment. Using the ViroSeq assay, only 23 of the 40 (57.5%) dried blood spot specimens were successfully genotyped; 22 of these specimens had plasma viraemia >10 000 RNA copies/mL. When the specimens were tested using the in-house assay, 38 of the 40 dried blood spots (95%) were successfully genotyped. Overall, resistance genotypes generated from the dried blood spots and plasma were highly concordant. The authors show that drug resistance genotyping from dried blood spots stored at 4 degrees C with desiccant is highly efficient but requires the amplification of small pol fragments and the use of an in-house nested PCR protocol with quality-controlled reagents. These findings suggest that 4 degrees Celsius may represent a suitable temperature for long-term storage of dried blood spots.

Editors´note: Dried blood spots are easy to transport, can be stored for long periods, and can be used now for a variety of micro-level diagnostic tests. The HIV drug resistance genotyping test described here would require product development to move it from an “in-house” modified test to a standardized procedure that could be used in national resistance surveillance.

van Sighem A, Zhang S, Reiss P, Gras L, van der Ende M, Kroon F, Prins J, de Wolf F; on Behalf of the ATHENA National Observational Cohort Study. Immunologic, Virologic, and Clinical Consequences of Episodes of Transient Viraemia During Suppressive Combination Antiretroviral Therapy. J Acquir Immune Defic Syndr. 2008 May 1;48(1):104-8.

van Sighem and colleagues aimed to investigate immunologic, virologic, and clinical consequences of episodes of transient viraemia in patients with sustained virologic suppression. From the AIDS Therapy Evaluation Project, Netherlands cohort, 4447 previously therapy-naive patients were selected who were on continuous combination antiretroviral therapy and had initial success (2 consecutive HIV RNA measurements <50 copies/mL). During episodes of viral suppression (RNA <50 copies/mL), low-level viraemia (RNA 50 to 1000 copies/mL), or high-level viraemia (RNA >1000 copies/mL) after initial success, the occurrence of therapy changes, drug resistance, and clinical events was assessed. During 11,187 person-years of follow-up, 1281 (28.8%) patients had at least 1 RNA measurement >50 copies/mL. Among 8069 episodes, there were 5989 (74.2%) episodes of suppression, 1711 (21.2%) episodes of low-level viraemia, and 369 (4.6%) episodes of high-level viraemia. Most episodes of low-level viraemia consisted of </=2 RNA measurements (93.7%), were without clinical events or therapy changes (79.6%), and were without changes in CD4 cell counts. Therapy changes (52.3% of episodes) and resistance (23.3%) were frequently observed during high-level viraemia. In conclusion, episodes of low-level viraemia are frequent and short-lasting, and the low proportion of episodes with clinical events suggests that leaving therapy unchanged is a clinically acceptable strategy. In contrast, high-level viraemia is associated with resistance and is often followed by therapy changes.

Editors´note: Although the focus here is on whether viraemia should be an indication for a change in therapy, viraemia in previously naive patients on treatment has potential relevance for transmission risk. A high proportion of patients were viraemic during winter when influenza and the common cold are more prevalent, suggesting that antigenic stimulation due to other infections may play a role. Thus, although effective antiretroviral treatment reduces viral load, blips can still occur – 28.8% of continuously treated patients in this large-cohort experienced at least one transient episode of viraemia.

Kwara A, Delong A, Rezk N, Hogan J, Burtwell H, Chapman S, Moreira CC, Kurpewski J, Ingersoll J, Caliendo AM, Kashuba A, Cu-Uvin S. Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. Clin Infect Dis. 2008;46(5):719-25.

Kwara and colleagues aimed to determine antiretroviral drug concentrations and human immunodeficiency virus (HIV) RNA rebound in cervicovaginal fluid in relation to blood plasma in women receiving suppressive highly active antiretroviral therapy. Thirty-four HIV-infected women who had plasma HIV RNA levels < or =80 copies/mL for at least 6 months were enrolled. Sixty-eight paired cervicovaginal fluid  and blood plasma  drug concentrations and HIV RNA levels were determined before and 3-4 h after drug administration. For each woman and antiretroviral drug, the cervicovaginal fluid:blood plasma  drug concentration ratios before and after drug administration were calculated. The nonparametric Wilcoxon rank sum test was used to determine if these ratios were different from 1.0. Lamivudine (administered to 20 patients) and tenofovir (administered to 16) had significantly higher concentrations in cervicovaginal fluid than in blood plasma  before drug administration, with mean cervicovaginal fluid:blood plasma  concentration ratios of 3.19 (95% confidence interval, 1.2-8.5) and 5.2 (95% confidence interval, 1.2-22.6), respectively. Efavirenz (administered to 13 patients) and lopinavir (administered to 6) had significantly lower concentrations in cervicovaginal fluid, with mean cervicovaginal fluid:blood plasma  concentration ratios of 0.01 (95% confidence interval, 0.00-0.03) and 0.03 (0.01-0.11), respectively. During the study visit (median time after enrolment, 6 months), blood plasma  and cervicovaginal fluid detectable HIV RNA levels were observed 7 patients (20.6%) and 1 patient (2.9%), respectively. Despite lower cervicovaginal fluid concentrations of key antiretroviral therapy components, such as efavirenz and lopinavir, virologic rebound was rare. The high concentrations of tenofovir and lamivudine in cervicovaginal fluid may have implications for the prevention of sexual transmission during antiretroviral therapy and for pre-exposure or post-exposure prophylaxis.

Editors´note: Both non-nucleoside reverse transcriptase inhibitors and protease inhibitors penetrate poorly into the genital tract achieving concentrations from 3 to 33% of their concentrations in paired blood plasma. Whether this creates the equivalent of local suboptimal therapy which could lead to genital tract viral drug resistance is not known. The good news is that the nucleoside reverse transcriptase inhibitors that form the backbone of combination therapy not only accumulate but actually concentrate in cervicovaginal fluid, which could have implications for prevention of onward HIV transmission.

Belza MJ, de la Fuente L, Suárez M, Vallejo F, García M, López M, Barrio G, Bolea A; Health And Sexual Behaviour Survey Group. Men who pay for sex in Spain and condom use: prevalence and correlates in a representative sample of the general population. Sex Transm Infect. 2008;84:207–211.

Belza and colleagues aimed to estimate the percentage of men who have paid for heterosexual sex in Spain and the percentage who used condoms. They aimed to identify the main factors associated with these behaviours and to describe opinions about condoms. Sexual behaviour probability sample survey in men aged 18–49 years resident in Spain in 2003 (n=5153). Computer-assisted face to face and self interview was used. Bivariate and multivariate logistic regression analyses were performed. 25.4% (n=1306) of the men had paid for heterosexual sex at some time in their lives; 13.3% (n=687) in the last 5 years and 5.7% (n=295) in the last 12 months. In the logistic analysis this behaviour was associated with older age, lower education, being unmarried, foreign birth, being a practicing member of a religious group, unsatisfactory communication with parents about sex, age under 16 years at first sexual intercourse and having been drunk in the last 30 days. Of the men who had paid for sex in the previous 5 years, 95% (n=653) had used a condom in the most recent paid contact. In the multivariate analysis, not using a condom was associated with age over 30 years and first sexual intercourse before age 16 years. Men who did not use condoms in the last commercial intercourse had more negative opinions about condoms. In conclusion, the prevalence of paying for heterosexual sex among Spanish men is the highest ever described in developed countries. The many variables associated with paying for sex and condom use permit the characterisation of male clients of prostitution and should facilitate targeting HIV prevention policies.

Editors´note: There have been many studies of female sex workers but little research on the prevalence of paying for sex in the general male population. This study is intriguing not only because condom use in these encounters is so high but because a quarter of men have paid for sex at some point in their lives. Aside from a number of expected associations, logistical regression found that practicing members of a religious group (94.4% of whom were Catholic) – defined as attending religious services once a week or more - had a higher prevalence of commercial sex relations and were less likely to use condoms in these encounters.

Watts DH, Park JG, Cohn SE, Yu S, Hitti J, Stek A, Clax PA, Muderspach L, Lertora JJ. Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093. Contraception. 2008;77(2):84-90. Epub 2007 Dec 21.

Concomitant use of antiretroviral drugs and hormonal contraceptives may change the metabolism of each and the resulting safety profiles. We evaluated the safety and tolerability of depot medroxyprogesterone acetate among women on antiretroviral drugs. HIV-infected women on selected antiretroviral drug regimens or no antiretroviral drugs were administered medroxyprogesterone acetate 150 mg intramuscularly and evaluated for 12 weeks for adverse events, changes in CD4+ count and HIV RNA levels, and ovulation. Seventy evaluable subjects were included, 16 on nucleoside only or no antiretroviral drugs, 21 on nelfinavir-containing regimens, 17 on efavirenz-containing regimens and 16 on nevirapine-containing regimens. Nine Grade 3 or 4 adverse events occurred in seven subjects; none were judged related to medroxyprogesterone acetate. The most common findings possibly related to medroxyprogesterone acetate were abnormal vaginal bleeding (nine, 12.7%), headache (three, 4.2%), abdominal pain, mood changes, insomnia, anorexia and fatigue, each occurring in two (2.9%) subjects. No significant changes in CD4+ count or HIV RNA levels occurred with DMPA. No evidence of ovulation was detected, and no pregnancies occurred. In conclusion, the clinical profile associated with medroxyprogesterone acetate administration in HIV-infected women, most on antiretroviral drugs, appears similar to that seen in HIV-uninfected women. medroxyprogesterone acetate prevented ovulation and did not affect CD4+ counts or HIV RNA levels. In concert with previously published medroxyprogesterone acetate/antiretroviral drugs interaction data, these data suggest that medroxyprogesterone acetate can be used safely by HIV-infected women on the antiretroviral drugs studied.

Editors´note: These results are reassuring, particularly for women on efavirenz, a drug with potential teratogenic effects. However, the number of study participants was small and this was a 12-week study. Long-term DMPA use is associated with increases in weight and fat distribution, which may be exacerbated by some antiretroviral drugs.

Unge C, Johansson A, Zachariah R, Some D, Van Engelgem I, Ekstrom AM. Reasons for unsatisfactory acceptance of antiretroviral treatment in the urban Kibera slum, Kenya. AIDS Care. 2008;20(2):146-9.

The aim of this study was to explore why patients in the urban Kibera slum, Nairobi, Kenya, offered free antiretroviral treatment at the Médecins Sans  Frontièrs (MSF) clinic, choose not to be treated despite signs of AIDS. Qualitative semi-structured interviews were conducted with 26 patients, 9 men and 17 women. Six main reasons emerged for not accepting antiretroviral treatment: a) fear of taking medication on an empty stomach due to lack of food; b) fear that side-effects associated with antiretroviral treatment would make one more ill; c) fear of disclosure and its possible negative repercussions; d) concern for continuity of treatment and care; e) conflicting information from religious leaders and community, and seeking alternative care (e.g. traditional medicine); f) illiteracy making patients unable to understand the information given by health workers.

Editors´note: The findings of this study guided the following urgent policy changes in the treatment programme: nutritional supplementation with ready-to-use food, adaptation of information pamphlets to local realities, alternative communication methods (peer groups, church, and traditional leaders), voluntary as opposed to mandatory disclosure to a `treatment buddy´, and enhanced links to other community partners in Kibera. Action-oriented research such as this explores problems and their underpinnings to create a platform for reality-based solutions.

Phillips EJ, Mallal SA. Pharmacogenetics and the potential for the individualization of antiretroviral therapy. Curr Opin Infect Dis. 2008;21(1):16-24.

Genetic associations highlighting differences in the response to HIV infection and treatment have significantly furthered our understanding of the pathogenesis, pharmacokinetics and pharmacodynamics of antiretroviral drug action and toxicities and HIV disease itself. This review focuses on the current knowledge of associations between polymorphisms and treatment outcomes in HIV with particular emphasis on clinically relevant relationships likely to lead to the individualization of antiretroviral therapy. Our understanding of the immunogenetic basis of drug toxicity has been furthered by human leukocyte antigen associations with hypersensitivities for the antiretroviral drugs abacavir and nevirapine. For abacavir in particular, the use of HLA-B*5701 as a screening test appears to be generalizable across racially diverse populations and has been supported by both observational, and blinded randomized controlled trials. Differences in HIV acquisition and progression as well as antiretroviral efficacy and toxicity will continue to provide the basis for research to define the genetic basis of such diversity. Despite the plethora of research in this area, numerous barriers exist to the successful operationalization of genetic testing to the clinic. HLA-B*5701 screening to prevent abacavir hypersensitivity is currently the most relevant to clinical practice and highlights that the promise of cost-effective testing can be facilitated by robust laboratory methodology and quality assurance programs that can be applied to diverse treatment settings.

Editors´note: Drug hypersensitivity syndromes are not directly related to the dose of a drug but are thought to be related to a combination of factors and associated with specific human leukocyte antigen (HLA) alleles within the major histocompatibility complex. In the case of patients starting nevirapine, 16% develop rash, 5% have hypersensitivity reactions with fever and hepatitis, and 0.3% can have severe skin syndromes. Knowledge of HIV pharmacogenetics is growing but unfortunately it will be some time before antiretroviral treatment in the real world can be tailored to patient genetics to avoid hypersensitivity reactions.

During the evolution, the immune system has developed several strategies to fight viral infections. Apoptosis, autophagy and necrosis are different types of cell death that play a main role in the interactions between infective agents and the host, since they are often important defence mechanisms that have to avoid the spreading of the infection. In turn, viruses have evolved numerous ways to evade the host immune system by influencing the behaviour and functionality of several components. HIV infects and kills CD4+ T helper lymphocytes, preferentially those that are antigen-specific, but also encodes proteins with apoptotic capacities, including gp120, gp160, Tat, Nef, Vpr, Vpu, Vif and, last but not least, the viral protease. This latter protein can kill infected and uninfected lymphocytes through the action of several host molecules, mainly members of the tumour necrosis factor family, or via the mitochondrial apoptotic pathway. The proinflammatory state that is characteristic of both the acute and chronic phase of HIV infection facilitates cell death, and is an additional cause of immune damage. Potent antiretroviral drugs that are largely used in therapy can reduce apoptosis by different mechanisms, that not only include the diminished production of the virus by infected cells and the subsequent reduction of inflammation, but also a direct action on the viral protease. The role of the host genetic background is finally crucial in understanding the process of cell death in HIV infection.

Editors´note: Programmed cell death or apoptosis is one of our most ancestral and potent cell defence mechanisms. HIV manipulates the apoptotic machinery to its advantage. For example, some viral proteins cause down- regulation of CD4 preventing gp120-CD4-mediated cell death. If HIV caused massive cell death, it couldn’t survive itself. On our side, we trigger activation of non-infected cells to help cope with the virus but then these innocent bystanders are induced to die by the virus. Research on immunogenetics can provide insights into why some people control HIV better, which may help with the design of antiretroviral therapy for immune reconstitution.

Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, Holmberg SD, Brooks JT; Adult and Adolescent Spectrum of Disease Project and HIV Outpatient Study Investigators. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med. 2008;148(10):728-36.

Persons who are HIV-infected may be at higher risk for certain types of cancer than the general population. Patel and colleagues conducted prospective observational cohort studies in the United States to compare cancer incidence among HIV-infected persons with incidence in the general population from 1992 to 2003. 54,780 HIV-infected persons in the Adult and Adolescent Spectrum of HIV Disease Project (47,832 patients) and the HIV Outpatient Study (6948 patients), who contributed 157,819 person-years of follow-up from 1992 to 2003, and 334,802,121 records from the Surveillance, Epidemiology, and End Results program of 13 geographically defined, population-based, central cancer registries were included. Standardized rate ratios were estimated to compare cancer incidence in the HIV-infected population with standardized cancer incidence in the general population. The incidence of the following types of non-AIDS-defining cancer was significantly higher in the HIV-infected population than in the general population: anal (standardized rate ratio, 42.9 [95% CI, 34.1 to 53.3]), vaginal (21.0 [CI, 11.2 to 35.9]), Hodgkin lymphoma (14.7 [CI, 11.6 to 18.2]), liver (7.7 [CI, 5.7 to 10.1]), lung (3.3 [CI, 2.8 to 3.9]), melanoma (2.6 [CI, 1.9 to 3.6]), oropharyngeal (2.6 [CI, 1.9 to 3.4]), leukaemia (2.5 [CI, 1.6 to 3.8]), colorectal (2.3 [CI, 1.8 to 2.9]), and renal (1.8 [CI, 1.1 to 2.7]). The incidence of prostate cancer was significantly lower among HIV-infected persons than the general population (standardized rate ratio, 0.6 [CI, 0.4 to 0.8]). Only the relative incidence of anal cancer increased over time. A study limitation was the lower ascertainment of cancer in the HIV cohorts which may result in a potential bias to underestimate rate disparities. Tobacco use as a risk factor and the effect of changes in cancer screening practices could not be evaluated. In conclusion, the incidence of many types of non-AIDS-defining cancer was higher among HIV-infected persons than among the general population from 1992 to 2003.

Editors´note: In addition to the significantly higher incidence of several types of cancer in people living with HIV compared to the general population, this study found increasing incidence rates over time for melanoma; Hodgkin lymphoma; and colorectal, anal, and prostate cancer, despite the advent of antiretroviral treatment. Both behavioural/lifestyle factors and other viruses (human papilloma virus, Epstein Barr Virus) may be implicated. In the case of HPV infection, prevention includes screening for early detection and treatment, along with evaluation of primary prevention measures such as vaccination and male circumcision.

Bock J, Johnson. Grandmothers’ Productivity and the HIV/AIDS Pandemic in sub-Saharan Africa. J Cross Cult Gerontol. 2008 Jan 8.

The human immunodeficiency virus (HIV) pandemic has left large numbers of orphans in sub-Saharan Africa. Botswana has an HIV prevalence rate of approximately 40% in adults. Morbidity and mortality are high, and in a population of a 1.3 million there are nearly 50,000 children who have lost one or both parents to HIV. The extended family, particularly grandparents, absorbs much of the childrearing responsibilities. This creates large amounts of additional work for grandmothers especially. The embodied capital model and the grandmother hypothesis are both derived from life history theory within evolutionary ecology, and both predict that one important factor in the evolution of the human extended family structure is that post-reproductive individuals such as grandmothers provide substantial support to their grandchildren’s survival. Data collected in the pre-pandemic context in a traditional multi-ethnic community in the Okavango Delta of Botswana are analyzed to calculate the amount of work effort provided to a household by women of different ages. Results show that the contributions of older and younger women to the household in term of both productivity and childrearing are qualitatively and quantitatively different. These results indicate that it is unrealistic to expect older women to be able to compensate for the loss of younger women’s contributions to the household, and that interventions be specifically designed to support older women based on the type of activities in which they engage that affect child survival, growth, and development.

Editors’ note: This study found that grandmothers are unable to substitute their labour for that of younger women lost to the family because of the energy intensity (strength and stamina) required for grain-processing. Further, the more time they allocate to food production, the less time they have for seeking and processing traditional wild foods that provide high levels of micronutrients and phytochemicals. They also can no longer produce traditional craft items such as the baskets, fishing implements, and tools essential to the productivity of all members of the household. Critically, their grandchildren have no means to acquire the skills and knowledge about traditional activities from them that are key to their long-term survival. Interventions to compensate for lost labour should support grandmothers in pursuing their traditional roles and activities.

This paper estimates the impact of antiretroviral therapy on days harvesting tea per month for tea-estate workers in Kenya. Such information is needed to assess the potential economic benefits of providing treatment to working adults. Data for this analysis come from company payroll records for 59 HIV-infected workers and a comparison group of all workers assigned to the same work teams (reference group, n = 1992) for a period covering 2 years before and 1 year after initiating antiretroviral therapy. Mean difference tests were used to obtain overall trends in days harvesting tea by month. A difference in difference approach was used to estimate the impact of HIV on days working in the pre-antiretroviral therapy period. Information on likely trends in the absence of the therapy was used to estimate the positive impacts on days harvesting tea over the initial 12 months on antiretroviral therapy. No significant difference existed in days plucking tea each month until the ninth month before initiating antiretroviral therapy, when workers worked -2.79 fewer days than references (15% less). This difference grew to 5.09 fewer days (27% less) in the final month before initiating antiretroviral therapy. After 12 months on antiretroviral therapy, Larson and colleagues conservatively estimate that workers worked at least twice as many days in the month than they would have in the absence of antiretroviral therapy. In conclusion treatment had a large, positive impact on the ability of workers to undertake their primary work activity, harvesting tea, in the first year on antiretroviral therapy.

Editors’ note: This study found that tea pluckers placed on antiretroviral treatment worked 7.5 to 9.5 days more harvesting tea in month 12 than they would have worked in the absence of antiretroviral treatment. A large cohort and a longer period of follow-up are required to determine the impact of antiretroviral treatment on work performance over the long term but these are promising initial findings.

Micheloud D, Berenguer J, Bellón JM, Miralles P, Cosin J, de Quiros JC, Conde MS,Muñoz-Fernández MA, Resino S. Negative influence of age on CD4+ cell recovery after highly active antiretroviral therapy in naive HIV-1-infected patients with severe immunodeficiency. J Infect. 2008 ;56(2):130-6.

Micheloud and colleagues aimed to study the effect of age on several outcomes among 187 antiretroviral-naive infected patients who started highly active antiretroviral therapy (HAART) with <or=200 CD4(+)/microl. The authors carried out a retrospective study to determine the hazard ratio (HR) to reach an outcome in patients who experienced a change from the baseline in CD4(+) counts of at least +100, +200, +300, +400 and +500 cells/microl at any moment during the follow-up and the odds ratio (OR) of achieving and maintaining a CD4(+) value above a certain setpoint during at least 6, 12 or 18 months. The adjusted HR for an increase of +400 CD4(+)/microl and +500 CD4(+)/microl were 1.3 (95% CI: 1.1; 1.5) and 1.3 (95% CI: 1.1; 1.6) times slower for each additional 5 years of age at baseline. In addition, for every 5 years of extra age, the adjusted OR to achieve an absolute CD4(+) cell count >500/microl at 6, 12 and 18 months after the initiation of HAART were 2.2 (95% CI: 1.5; 3.2), 1.8 (95% CI: 1.2; 2.6), and 1.8 (95% CI: 1.2; 2.9) times less likely, respectively. The authors also found that patients >or=45 years old had worse complete CD4(+) recovery (CD4(+)>500 cells/microl) than patients <45 years old. in conclusion, the CD4(+) recovery after HAART is a prolonged and continuous process which extends for several years. Age at baseline is inversely correlated with the magnitude and speed of CD4(+) recovery among HIV-1 infected patients.

Editors’ note: Older age at the time of HIV acquisition is associated with faster disease progression. This study found that increasing age was associated with slower CD4 count recovery after initiation of antiretroviral treatment and a lower likelihood of reaching an absolute CD4 count of 500. This suggests that older people may benefit from earlier initiation of antiretroviral treatment before CD4 counts reach 200.

The aim of this study was to estimate the outcome and cost-effectiveness per life-year-gained (LYG) of first-, second- and third-line non-nucleoside reverse transcriptase inhibitors (NNRTI) versus protease inhibitor (PI) containing highly active antiretroviral therapy regimens. Hospital care costs (2002 US dollars discounted 3.5% per annum) were linked to treatment failure times. Results show that the median time-to-treatment failure for first-line (nucleoside reverse transcriptase inhibitors) 2NRTIs + NNRTI was substantially longer than that for 2NRTIs + PI (boosted), 2NRTIs + PI and 2NRTIs + 2PIs, whereas for second- and third-line they were similar. Comparing first-line 2NRTIs + NNRTI with 2NRTIs + PI (boosted) cost per LYG was US$ 12,375; US$ 12,139 per LYG when compared with 2NRTIs + PI and US$ 2948 per LYG when compared with 2NRTIs + 2PIs. For second-line cost per LYG comparing 2NRTIs + NNRTI with 2NRTIs + PI (boosted) was US$ 19,501; US$ 18,364 per LYG when compared with 2NRTIs + PI and cost-saving when compared with 2NRTIs + 2PIs. For third-line cost per LYG comparing 2NRTIs + NNRTI with 2NRTIs + PI(boosted) was US$ 2708; US$ 11,559 per LYG when compared with 2NRTIs + PI and cost-saving when compared with 2NRTIs + 2PIs. In conclusion, first-line 2NRTIs + NNRTI was cost-effective or cost-saving when compared with PI-containing regimens for all lines of therapy. Such information is required by clinicians and managers of HIV services to make appropriate treatment decisions based on clinical and financial grounds, and given the increasing number of people living with HIV, such information will become more important over time.

Editors’ note: In low- and middle–income countries, the standard first-line therapy recommended by the WHO public health approach contains a backbone of two nucleoside reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase inhibitor (2 nukes and 1 non-nuke). Until now, the outcome and cost-effectiveness of such regimens compared to protease inhibitor (PI) containing regimens have not been studied. Although the setting for this study is a high-income country, the 2 nukes-1 non-nuke first-line, second-line, and third-line regimens were either cost-effective or cost-saving. Of note is the much longer median time to treatment failure for people on these first-line regimens compared to those containing protease inhibitors, a finding of direct relevance for low- and middle-income countries.

Jahn A, Floyd S, Crampin AC, Mwaungulu F, Mvula H, Munthali F, McGrath N, Mwafilaso J, Mwinuka V, Mangongo B, Fine PE, Zaba B, Glynn JR. Population-level effect of HIV on adult mortality and early evidence of reversal after introduction of antiretroviral therapy in Malawi. Lancet. 2008;371(9624):1603-11.

Malawi, which has about 80,000 deaths from AIDS every year, made free antiretroviral therapy available to more than 80 000 patients between 2004 and 2006. Jahn and colleagues aimed to investigate mortality in a population before and after the introduction of free antiretroviral therapy, and therefore to assess the effects of such programmes on survival at the population level. The authors used a demographic surveillance system to measure mortality in a population of 32,000 in northern Malawi, from August, 2002, when free antiretroviral therapy was not available in the study district, until February, 2006, 8 months after a clinic opened. Causes of death were established through verbal autopsies (retrospective interviews). Patients who registered for antiretroviral therapy at the clinic were identified and linked to the population under surveillance. Trends in mortality were analysed by age, sex, cause of death, and zone of residence. Before antiretroviral therapy became available in June, 2005, mortality in adults (aged 15-59 years) was 9.8 deaths for 1000 person-years of observation (95% CI 8.9-10.9). The probability of dying between the ages of 15 and 60 years was 43% (39-49) for men and 43% (38-47) for women; 229 of 352 deaths (65.1%) were attributed to AIDS. 8 months after the clinic that provided antiretroviral therapy opened, 107 adults from the study population had accessed treatment, out of an estimated 334 in need of treatment. Overall mortality in adults had decreased by 10% from 10.2 to 8.7 deaths for 1000 person-years of observation (adjusted rate ratio 0.90, 95% CI 0.70-1.14). Mortality was reduced by 35% (adjusted rate ratio 0.65, 0.46-0.92) in adults near the main road, where mortality before antiretroviral therapy was highest (from 13.2 to 8.5 deaths per 1000 person-years of observation before and after antiretroviral therapy). Mortality in adults aged 60 years or older did not change. The findings of a reduction in mortality in adults aged between 15 and 59 years, with no change in those older than 60 years, suggests that deaths from AIDS were averted by the rapid scale-up of free antiretroviral therapy in rural Malawi, which led to a decline in adult mortality that was detectable at the population level.

Editors’ note: With no vital registration system in place or reliable mortality statistics reported from health services, this study established a continuous registration demographic surveillance system after completing a household census in Karonga district (pop. 32,000). A child born into this population before the introduction of antiretroviral therapy had a 37% lifetime risk of dying from AIDS. This surveillance system demonstrated that by 8 months after the free antiretroviral treatment programme began, overall mortality in adults aged 15-59 had decreased by 10%. Only a third of adults in need of treatment had been started on antiretroviral treatment so population mortality should continue to fall as access to treatment is decentralized and scaled up.

Bennett D, Myatt M, Bertagnolio S, Sutherland D, Gilks C. Recommendations for surveillance of transmitted HIV drug resistance in countries scaling up antiretroviral treatment. Antivir Ther 2008; Supplement 2: 25–36.

The World Health Organization (WHO) HIV drug resistance threshold survey method was developed for surveillance of transmitted HIV drug resistance in resource-limited countries. The method is being implemented with minimal resources as a routine public health activity to produce comparable results in multiple countries and areas within countries. Transmitted drug resistant HIV strains will be seen first in cities or health districts where antiretroviral treatment has been widely available for years. WHO recommends countries begin surveillance in these areas. Each survey requires <=47 specimens from individuals consecutively diagnosed with HIV to categorize resistance to each relevant drug class as <5%, 5–15% or >15%. Use of routinely collected information and remnant specimens is recommended to minimize costs. Site and individual eligibility criteria are designed to minimize inclusion of antiretroviral drug-experienced individuals and individuals infected before antiretroviral treatment was available. Surveys have been implemented in 21 countries. In this supplement, seven countries report results of <5% transmitted HIV drug resistance in areas where antiretroviral treatment has been available for the longest time period. The main challenges in implementation are acquiring sufficient numbers of eligible specimens and optimizing specimen handling. The WHO HIV drug resistance threshold survey method is feasible in resource-limited countries and produces information relevant to antiretroviral treatment and drug resistance prevention planning.

Editors’ note: This supplement contains reports of HIV drug resistance surveillance from seven countries ( Ethiopia, Malawi, Swaziland, Tanzania, Vietnam, South Africa, and Thailand) along with methodological articles explaining the threshold survey analysis method. This method requires minimal infrastructure and provides important information to limit the emergence and transmission of resistance in resource-limited settings.

Malawi started rapid scale-up of antiretroviral therapy in 2004 and by December 2006 had initiated over 85,000 patients on treatment. Early warning indicator reports can help to minimize the risk of emerging drug resistance. Data collected during the routine quarterly supervision of 103 public sector sites was used to compile the first early warning indicator report for HIV drug resistance in Malawi, reflecting outcomes for October to December 2006. All sites reach the World Health Organization (WHO) targets for prescribing practices and drug supply continuity. The target for adherence was achieved by 85% of sites and 84% achieved the target for minimizing treatment defaults; however, less than half of all sites reach the WHO target for patient retention. In conclusion, these results emphasize the importance of defaulter tracing and initiating treatment earlier in the course of HIV infection. As part of a comprehensive HIV drug resistance monitoring programme, the Ministry of Health plans for on-going tracking of these indicators, as well as special data collection from the private sector. Plans are also underway to gather information on other recommended indicators that are not collected during routine supervision.

Editors’ note: In Malawi, data on programmatic factors associated with an increased risk of drug resistance such as patient adherence, prescribing practices, continuity of drug supply, and patient outcomes are reviewed with site personnel during routine quarterly supervision visits. National patient mastercards (the patient record) and patient antiretroviral registers are complimented by pharmacy registers. With monthly targets for new patients starting HIV treatment set nationally, drug procurement can be accurately estimated and drugs reallocated if necessary to prevent the stock-outs that are a prominent cause of drug resistance.

Husbands W, Browne G, Caswell J, Buck K, Braybrook D, Roberts J, Gafni A, Taylor A. Case management community care for people living with HIV/AIDS (PLHAs). AIDS Care 2007; 19:1065-72.

A case management approach to support services was developed in a Toronto-based AIDS service organization in Canada to support people living with HIV whose needs could not be addressed through usual self-directed access to services. It was therefore important to determine which persons would benefit most from case management. New clients and those who had been receiving support services from an AIDS service organization were randomized to receive either self-directed use of support services or self-directed care plus strengths-based case management for a six-month period. Those who benefited most from case management were very depressed at baseline. Strengths-based case management compared to usual self-directed care markedly improved the physical, social, and mental health function of very depressed persons living with HIV, and reduced their risk behaviours. In addition, the case management participants’ use of community services was associated with an economically important, though not statistically significant, $3,300 per person per annum lower expenditure for the use of all direct health and social services. Although more research is warranted, this research demonstrates that AIDS service organizations and funders ought to seriously consider implementing a case management approach to practical assistance for persons living with HIV with depression.

Editors’ note: Placing very depressed patients with a case manager who can assist them in becoming functional was found to be good value for money invested and improved quality of life. The lower expenditure on all services used by people living with HIV who received case management more than offset the cost of case managers, under a system of national health care insurance.

Tejiokem MC, Gouandjika I, Béniguel L, Zanga MC, Tene G, Gody JC, Njamkepo E,Kfutwah A, Penda I, Bilong C, Rousset D, Pouillot R, Tangy F, Baril L. HIV-Infected Children Living in Central Africa Have Low Persistence of Antibodies to Vaccines Used in the Expanded Program on Immunization. PLoS ONE. 2007; 2(12):e1260.

The Expanded Program on Immunization is the most cost-effective measure to control vaccine-preventable diseases. Currently, the Expanded Program on Immunization schedule is similar for HIV-infected children; the introduction of antiretroviral therapy should considerably prolong their life expectancy. To evaluate the persistence of antibodies to the Expanded Program on Immunization vaccines in HIV-infected and HIV-exposed uninfected children who previously received these vaccines in routine clinical practice, Tejiokem and colleagues conducted a cross-sectional study of children, aged 18 to 36 months, born to HIV-infected mothers and living in Central Africa. The authors tested blood samples for antibodies to the combined diphtheria, tetanus, and whole-cell pertussis (DTwP), the measles and the oral polio (OPV) vaccines. They enrolled 51 HIV-infected children of whom 33 were receiving antiretroviral thearpy, and 78 HIV-uninfected children born to HIV-infected women. A lower proportion of HIV-infected children than uninfected children had antibodies to the tested antigens with the exception of the OPV types 1 and 2. This difference was substantial for the measles vaccine (20% of the HIV-infected children and 56% of the HIV-exposed uninfected children, p<0.0001). There was a high risk of low antibody levels for all Expanded Program on Immunization vaccines, except OPV types 1 and 2, in HIV-infected children with severe immunodeficiency (CD4(+) T cells <25%). Children were examined at a time when their antibody concentrations to Expanded Program on Immunization vaccines would have still not undergone significant decay. However, the authors showed that the antibody concentrations were lowered in HIV-infected children. Moreover, antibody concentration after a single dose of the measles vaccine was substantially lower than expected, particularly low in HIV-infected children with low CD4(+) T cell counts. This study supports the need for a second dose of the measles vaccine and for a booster dose of the DTwP and OPV vaccines to maintain the antibody concentrations in HIV-infected and HIV-exposed uninfected children.

Editors’ note: Although more research is needed to better understand altered immune responses in uninfected infants born to HIV-positive women, it is clear from this study that there is an urgent need to study the effects of early initiation of antiretroviral therapy on responses to vaccines in children with HIV infection. In the meantime, booster doses would seem a pragmatic approach.

The survival of children with HIV has increased considerably with the use of more effective antiretrovirals, but the benefits of this therapy are limited by the difficulty of adherence to the treatment. This cross-sectional study aimed to estimate the prevalence of non-adherence to antiretrovirals among children residents in Porto Alegre, Rio Grande do Sul State, Brazil, and identifying associated factors. There were 194 child caregivers interviewed. The technique utilized to evaluate adherence allowed the detection of lack of understanding of the prescribed antiretroviral regimens, as well as conscious loss of doses. Non-adherence was defined when the child had taken less than 80% of the prescribed medication during the 24 h period prior to the interview. A general prevalence of non-adherence was 49.5%, which was higher than that estimated. The non-institutional caregivers had a prevalence rate of 55.7%, while the institutional caregivers had 22.2%. In multivariate analysis, the education of the caregiver was found to have a borderline association with the outcome. Institutionalized children and those taken care of by people with a higher educational level appeared to have more protection against non-adherence to antiretroviral therapy.

Editors’ note: For a country that guarantees free access to antiretroviral drugs, this high non-adherence rate is surprising. Non-adherence to antiretroviral treatment in children is clearly dependent on caretaker knowledge, attitudes, and behaviour. These are in part influenced by the type (relative or not) and quality of relationship between the caregiver and the child, and educational level of the caregiver. A stronger emphasis on monitoring caregivers is needed to protect children.

Burkitt’s lymphoma was first described in Eastern Africa, initially thought to be a sarcoma of the jaw. Shortly it became well known that this was a distinct form of Non Hodgkin’s lymphoma. The disease has given insight in all aspects of cancer research and care. Its peculiar epidemiology has led to the discovery of Epstein Barr virus and its importance in the cause of several viral illnesses and malignancies. The highest incidence and mortality rates of Burkitt’s lymphoma are seen in Eastern Africa. Burkitt’s lymphoma affects mainly children, and boys are more susceptible than girls. Evidence for a causal relationship between Epstein Barr virus and Burkitt’s lymphoma in the endemic form is fairly strong. Frequency of association between Epstein Barr virus and Burkitt’s lymphoma varies between different patient groups and different parts of the world. Epstein Barr virus may play a role in the pathogenesis of Burkitt’s lymphoma by deregulation of the oncogene c-MYC by chromosomal translocation. Although several studies suggest an association between malaria and Burkitt’s lymphoma, there has never been a conclusive population study in support of a direct role of malaria in causation of Burkitt’s lymphoma. The emergence of HIV and a distinct subtype of Burkitt’s lymphoma in HIV-infected have brought a new dimension to the disease particularly in areas where both HIV and Burkitt’s lymphoma are endemic. Burkitt’s lymphoma has been reported as a common neoplasm in HIV-infected patients, but not in other forms of immuno-depression, and the occurrence of Burkitt’s lymphoma seems to be higher amongst HIV-positive adults, while the evidence of an association amongst children is still disputed. The role of other possible risk factors such as low socio-economical status, exposure to a plant species common in Africa called Euphorbiaceae, exposure to pesticides and to other infections such as schistosomiasis and arbovirus (an RNA virus transmitted by insect vectors) remain to be elucidated.

Editors’ note: Burkitt’s lymphoma, which affects mainly children in Eastern Africa, is on the rise suggesting a possible association with HIV infection. In adults, increasing incidence has been seen in both Kenya and Uganda, which is not surprising given HIV prevalence and the known association between Epstein Barr virus infection and Burkitt’s lymphoma.

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.

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.