Operational research and HIV policy and guidelines: lessons from a study of patients lost to follow-up from a public antiretroviral treatment program in Cameroon.

Can operations and implementation research guide today's unprecedented efforts to scale-up HIV/AIDS prevention, treatment, care, and support in resource-limited settings? Our study of patients with HIV/AIDS who were first seen at the Central Hospital (Yaoundé, Cameroon) to begin antiretroviral therapy demonstrates the value of using operations research to explore programs, policies, and guidelines used in health care. We studied one group of patients, those lost to follow-up. Our findings confirmed the value of early treatment, systems to follow individuals, free treatment, and resources that enable operations research. We encourage health-care workers and program managers to perform operational research in their own context, and we emphasize the importance of allocating adequate human, financial, and logistic resources for this activity. Finally, we stress that the health-care workers, program managers, and researchers must work together to better inform policy and guidelines.

Lamivudine-resistant HBV infection in HIV-positive patients receiving antiretroviral therapy in a public routine clinic in Cameroon.

BACKGROUND: In Africa, most HIV-HBV-coinfected patients on antiretroviral therapy (ART) receive an anti-HBV lamivudine monotherapy that has been shown in northern countries to lead to frequent emergence of drug resistance. We assessed the HBV prevalence and the rate and pattern of lamivudine-resistant HBV mutations in Cameroonian HIV-infected, ART-treated patients. METHODS: A cross-sectional survey was performed in 2006-2007 at the HIV/AIDS outpatient clinic of the Central Hospital in Yaoundé, Cameroon. Plasma samples were tested as appropriate for hepatitis B surface antigens, antibodies to hepatitis B core, HBV DNA, genotypes and lamivudine-resistant polymerase mutations. RESULTS: Of 552 adult patients (71% women, median age 38 years), 290 had received lamivudine-based ART for 12 months and 262 for 24 months. No patient had received tenofovir. The prevalence of hepatitis B surface antigen was 9.8%. Overall, 26% of seropositive patients had an HBV DNA level >40 IU/ml. Genotypes A and E were identified. Polymerase resistance mutations were detected in 14% and 60% of patients at months 12 and 24, respectively. CONCLUSIONS: This study supports both WHO recommendations of screening for HBV before initiation of ART and of using ART containing tenofovir and either lamivudine or emtricitabine in HIV-HBV-coinfected patients in Africa.

Monitoring of HIV viral loads, CD4 cell counts, and clinical assessments versus clinical monitoring alone for antiretroviral therapy in rural district hospitals in Cameroon (Stratall ANRS 12110/ESTHER): a randomised non-inferiority trial.

BACKGROUND: Scaling up of antiretroviral therapy in low-resource countries is done on the basis of decentralised, integrated HIV care in rural facilities; however, laboratory monitoring is generally unavailable. We aimed to assess the effectiveness and safety of clinical monitoring alone (CLIN) in terms of non-inferiority to laboratory and clinical monitoring (LAB). METHODS: We did a randomised, open-label, non-inferiority trial in nine rural district hospitals in Cameroon. Eligible participants were adults (≥18 years) infected with HIV-1 group M (WHO disease stage 3-4) who had not previously received antiretroviral therapy, and were followed-up for 2 years by health-care workers in routine activities. We randomly assigned participants (1:1) to CLIN or LAB (counts of HIV viral load and CD4 cell every 6 months) groups with a computer-generated list. The primary outcome was non-inferiority of CLIN to LAB in terms of increase in CD4 cell count with a non-inferiority margin of 25%. We did all analyses in participants who attended at least one follow-up visit. This trial is registered with ClinicalTrials.gov, number NCT00301561. FINDINGS: 238 (93%) of 256 participants assigned to CLIN and 221 (93%) of 237 assigned to LAB were eligible for analysis. CLIN was not non-inferior to LAB; the mean increase in CD4 cell count was 175 cells per µL (SD 190, 95% CI 151-200) with CLIN and 206 (190, 181-231) with LAB (difference -31 [-63 to 2] and non-inferiority margin -52 [-58 to -45]). Furthermore, in the predefined secondary outcome of treatment changes, 13 participants (6%) in the LAB group switched to second-line regimens whereas no participants in the CLIN group did so (p<0·0001). By contrast, other predefined secondary outcomes were much the same in both groups-viral suppression (<40 copies per mL; 465 [49%] of 952 measurements in CLIN vs 456 [52%] of 884 in LAB), HIV resistance (23 [10%] of 238 participants vs 22 [10%] of 219 participants), mortality (44 [18%] of 238 vs 32 [14%] of 221), disease progression (85 [36%] of 238 vs 64 [29%] of 221), adherence (672 [63%] of 1067 measurements vs 621 [61%] of 1011), loss to follow-up (21 [9%] of 238 vs 17 [8%] of 221), and toxic effects (46 [19%] of 238 vs 56 [25%] of 221). INTERPRETATION: Our findings support WHO's recommendation for laboratory monitoring of antiretroviral therapy. However, the small differences that we noted between the strategies suggest that clinical monitoring alone could be used, at least temporarily, to expand antiretroviral therapy in low-resource settings. FUNDING: French National Agency for Research on AIDS (ANRS) and Ensemble pour une Solidarité Thérapeutique Hospitalière En Réseau (ESTHER).

WHO clinical criteria-based initiation of antiretroviral therapy: lessons from rural district hospitals in Cameroon with regard to 2009 revised WHO recommendations.

OBJECTIVE: To assess the proportion of patients infected with HIV with a CD4 count above 350 cells/mm(3) among those classified at WHO clinical stage 3 or 4 who initiated antiretroviral therapy in rural district hospitals in Cameroon to assess the 2009 revised WHO recommendations. METHODS: Cross-sectional study in nine rural district hospitals where the treatment initiation is based on the WHO clinical criteria. The proportion of patients who were classified at stage 3 or 4 and who had a CD4 count >350 cells/mm(3) was assessed. RESULTS: Of 458 patients included in 2006-2008 (women 70.5%; median age 37.0 years), 337 (73.6%) were classified at WHO clinical stage 3 and 121 (26.4%) at stage 4. Overall, 108 patients (23.6%) had a CD4 count >350 cells/mm(3). Of them, 94 patients (20.5%) were classified at WHO clinical stage 3, and 14 (3.1%) were classified at WHO clinical stage 4. CONCLUSION: The WHO clinical stages 3 and 4 were poorly correlated with the 'gold standard' of CD4 cell count. This study highlights the need to promote CD4 testing for assessing the patient eligibility.

Hepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon.

BACKGROUND: Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) in HIV-infected patients receiving a commonly used nevirapine-based antiretroviral therapy is a major concern for African clinicians owing to its high prevalence, the infrequent testing and treatment of viral hepatitis, and the impact of liver disease on the tolerability and effectiveness of anti-HIV treatment. We compared the hepatotoxicity and the immunological, virological and clinical effectiveness of a nevirapine-based antiretroviral therapy between patients infected with HIV only and patients coinfected with hepatitis B or C virus in Cameroon. METHODS: A retrospective cohort study was conducted among HIV-1-infected patients. Plasma HBV DNA and HCV RNA were tested in positive or indeterminate samples for HBsAg or HCV antibodies, respectively. All patients received nevirapine and lamivudine plus stavudine or zidovudine. RESULTS: Of 169 HIV-1-infected patients with a median baseline CD4 count of 135 cells/mm3 (interquartile range [IQR] 67-218), 21% were coinfected with HBV or HCV. In coinfected patients, the median viral load was 2.47 x 107 IU/mL for HBV (IQR 3680-1.59 x 108) and 928 000 IU/mL for HCV (IQR 178 400-2.06 x 106). Multivariate analyses showed that the risk of hepatotoxicity was 2-fold higher in coinfected patients (p < 0.01). The response to antiretroviral therapy was however comparable between monoinfected and coinfected patients in terms of CD4 cell count increase (p = 0.8), HIV-1 viral load below 400 copies/mL (p = 0.9), death (p = 0.3) and death or new AIDS-defining event (p = 0.1). Nevirapine was replaced by a protease inhibitor in 4 patients owing to hepatotoxicity. CONCLUSION: This study suggests that the nevirapine-based antiretroviral therapy could be used safely as first-line treatment in patients with low CD4 cell count in Africa despite frequent coinfections with HBV or HCV and infrequent testing of these infections. Although testing for HBV and HCV should be systematically performed before initiating antiretroviral therapy, transaminases elevations at baseline or during treatment should be a decisive argument for testing when hepatitis status is unknown.

Low levels of antiretroviral-resistant HIV infection in a routine clinic in Cameroon that uses the World Health Organization (WHO) public health approach to monitor antiretroviral treatment and adequacy with the WHO recommendation for second-line treatment.

A cross-sectional study, performed at a routine human immunodeficiency virus (HIV)/AIDS clinic in Cameroon that uses the World Health Organization public health approach, showed low rates of virological failure and drug resistance at 12 and 24 months after initiation of antiretroviral therapy. Importantly, the cross-sectional study also showed that the World Health Organization recommendation for second-line treatment would be effective in almost all patients with HIV drug resistance mutations.

Tolerability and effectiveness of first-line regimens combining nevirapine and lamivudine plus zidovudine or stavudine in Cameroon.

We compared the tolerability and effectiveness of two major first-line regimens used in resource-limited settings, namely zidovudine-lamivudine-nevirapine and stavudine-lamivudine-nevirapine. HIV-1-infected adults in Cameroon were enrolled in a prospective cohort study between 2001 and 2003. They were eligible if they had AIDS or a CD4 cell count below 350/mm(3), a Karnofsky score over 50%, and no contraindications to antiretroviral treatment. The patients were followed up to 2 years. Of 169 patients, 85 received zidovudine-lamivudine-nevirapine and 84 stavudine-lamivudine-nevirapine. The incidence rates of treatment changes, death, drug resistance, and severe adverse effects were, respectively, 12.0 [95% confidence interval (CI) 7.2-19.9] and 10.9 (CI 6.4-18.3) per 100 person-years; 5.7 (CI 2.8-11.4) and 7.6 (CI 4.2-13.7); 2.9 (CI 1.1-7.7) and 5.0 (CI 2.4-10.6); and 41.7 (CI 30.2-57.6) and 49.1 (CI 36.1-66.6). The Kaplan-Meier curves for the likelihood of remaining on the initial regimen (p = 0.8) and for survival (p = 0.5) did not differ significantly between the groups. In Cox multivariate analysis only a lower baseline CD4 cell count was associated with death (p < 0.001). The proportion of patients with undetectable viral load and the increase in the CD4 cell count were similar in the two groups. Anemia was rare (4% vs. 6%). Five cases of severe peripheral neuropathy and one case of lipodystrophy occurred. This study suggests that the zidovudine-lamivudine-nevirapine combination is a safe first-line treatment, even in settings with few laboratory resources. In view of stavudine toxicity, these results support recommendations calling for a gradual switch from stavudine- to zidovudine-based regimens.

Antiretroviral drug resistance and routine therapy, Cameroon.

Among 128 patients routinely receiving highly active antiretroviral therapy in an HIV/AIDS outpatient clinic in Cameroon, 16.4% had drug resistance after a median of 10 months. Of these, 12.5% had resistance to nucleoside reverse transcriptase inhibitors (NRTIs), 10.2% to non-NRTIs, and 2.3% to protease inhibitors.

Prevalence of intestinal parasites including microsporidia in human immunodeficiency virus-infected adults in Cameroon: a cross-sectional study.

To assess the prevalence of intestinal parasites in a cohort of human immunodeficiency virus (HIV)-infected adults in Cameroon, a cross-sectional study was conducted. Detection of parasites was performed in 181 stool samples from 154 HIV-infected patients with a mean CD4 cell count of 238 cells/mm(3). Only 35 patients (22%) were receiving antiretroviral therapy at the time of stool sampling, and 46 (29%) had diarrhea. Opportunistic protozoa were found in 15 patients (9.7%), 8 of whom (53%) had diarrhea. Enterocytozoon bieneusi was found in eight patients, C. parvum in six patients, and Isospora belli in three patients. All E. bieneusi isolates tested belonged to the same genotype. The prevalence of opportunistic protozoa among patients with CD4 cell counts less than 50/mm(3) was 32%.

Field assessment of generic antiretroviral drugs: a prospective cohort study in Cameroon.

OBJECTIVE: To assess the effectiveness of generic anti-retroviral drugs in terms of survival and virological and immunological responses, as well as their tolerability and the emergence of viral resistance. METHODS: A total of 109 HIV-1-infected patients were enrolled in a prospective cohort study in Yaoundé, Cameroon. Available generic drugs were a fixed-dose combination (FDC) of zidovudine (ZDV) and lamivudine (3TC), an FDC of 3TC, stavudine (d4T) and nevirapine (NVP), and individual formulations of ZDV, 3TC and NVP. RESULTS: At baseline, the median CD4 cell count was 150/mm3 [interquartile range (IQR) 61-223] and median viral load was 5.4 log10 copies/ml (IQR 4.8-5.6); 78% of patients received ZDV/3TC/NVP and 22% received 3TC/d4T/NVP. Median follow-up was 16 months (IQR 11-23). The survival probability was high (0.92 at 12 months); plasma viral load declined by a median of 3.3 log10 copies/ml and 86.9% of the intention-to-treat population had viral load <400 copies/ml at 12 months; CD4 count had increased by a median of 106 cells/mm3 at 12 months; drug resistance rarely emerged (incidence rate 3.2 per 100 person-years); and the treatments were reasonably well-tolerated (incidence rate of severe adverse effects 7.8 per 100 person-years). CONCLUSION: Together with previous pharmacological and clinical studies, this prospective study suggests that these generic antiretroviral drugs can be used in developing countries.

Commercial logging and HIV epidemic, rural Equatorial Africa.

We found a high seroprevalence of HIV among young women in a commercial logging area in Cameroon. The vulnerability of these young women could be related to commercial logging and the social and economic networks it induces. The environmental changes related to this industry in Equatorial Africa may facilitate HIV dissemination.

Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial.

BACKGROUND: Generic fixed-dose combinations have been prequalified by WHO to treat HIV-infected patients in resource-limited countries. Despite their widespread use they are, however, not yet recommended by some of the major donor agencies owing to scarcity of clinical data on effectiveness, safety, and quality. We aimed to assess these issues for one of the most frequently prescribed treatments in Africa, a generic fixed-dose combination of nevirapine, stavudine, and lamivudine. METHODS: 60 patients were followed in an open-label, 24-week multicentre trial in Cameroon. All patients received one tablet of the fixed-dose combination drug twice daily. The primary outcome measure was the proportion of patients with viral load less than 400 copies per mL at the end of the study period, in an intention-to-treat analysis. FINDINGS: At baseline, 92% of patients (n=55) had AIDS; median CD4 count was 118 cells per microL (IQR 78-167) and median plasma HIV-1 RNA was 104?736 copies per mL (40804-243787). The proportion of patients with undetectable viral load (<400 copies per mL) after 24 weeks of treatment was 80% (95% CI 68-89). Median (IQR) change in viral load was -3.1 log10 copies per mL (-2.5 to -3.6) and in CD4 count 83 cells per microL (40-178). The probability of remaining alive or free of new AIDS-defining events was 0.85 (95% CI 0.73-0.92). Frequency of disease progression was 32.0 (95% CI 16.6-61.5), severe adverse effects 17.8 (7.4-42.7), and genotypic resistance mutations 7.1 (1.8-28.4) per 100 person-years. Mean reported adherence rate was 99%. Median drug concentrations in tablets were 96% of expected values for nevirapine, 89% for stavudine, and 99% for lamivudine. INTERPRETATION: Our findings lend support to use and funding of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine as first-line antiretroviral treatment in developing countries.

Biological and genetic characteristics of HIV infections in Cameroon reveals dual group M and O infections and a correlation between SI-inducing phenotype of the predominant CRF02_AG variant and disease stage.

In Yaounde, Cameroon, HIV-1 group-specific V3 serology on 1469 HIV-positive samples collected between 1996 and 2001 revealed that group O infections remained constant around 1% for 6 years. Only one group N sample was identified and 4.3% reacted with group M and O peptides. Although the sensitivity of the group-specific polymerase chain reaction (PCR) in two genomic regions was not optimal, we confirmed, in at least 6 of 49 (12.2%) dual O/M seropositive samples and in 1 of 9 group O samples, dual infection with group O and M viruses (n = 4) or with group O or M virus and an intergroup recombinant virus (n = 3). Partial env (V3-V5) sequences on a subset of 295 samples showed that at least eight subtypes and five circulating recombinant forms (CRFs) of HIV-1 group M co-circulate; more than 60% were CRF02_AG and 11% had discordant subtype/CRF designations between env and gag. Similarly as for subtype B, the proportion of syncytium-inducing strains increased when CD4 counts were low in CRF02_AG-infected patients. The V3-loop charge was significantly lower for non-syncytium-inducing strains than for syncytium-inducing strains but cannot be used as an individual marker to predict phenotype. The two predominant HIV-1 variants in Africa, CRF02_AG and subtype C, thus have different biological characteristics.

No difference in clinical progression between patients infected with the predominant human immunodeficiency virus type 1 circulating recombinant form (CRF) 02_AG strain and patients not infected with CRF02_AG, in Western and West-Central Africa: a four-year prospective multicenter study.

To compare human immunodeficiency virus (HIV) type 1 disease progression in patients infected by the predominant strain circulating recombinant form (CRF) 02_AG in western and west-central Africa and in patients infected by other strains, a prospective multicenter cohort study was conducted in Cameroon and Senegal. Among the 335 patients, a broad HIV-1 group M subtype diversity was observed in the envelope V3-V5 region, but strain CRF02_AG predominated in both Cameroon and Senegal (61.2% and 62.9%, respectively; P<.8). Multivariate analyses showed no difference between patients infected by CRF02 strains and those infected by other strains in terms of survival (adjusted hazards ratio [HR], 1.16; 95% confidence interval [CI], 0.76-1.78; P=.5), clinical disease progression (HR, 0.79; 95% CI, 0.50-1.25; P=.3), or square root CD4 cell decline (regression coefficient, -0.01; 95% CI, -0.82 to 0.81; P=.9). This study suggests that the predominance of HIV-1 CRF02_AG strain in western and west-central Africa should have no major clinical consequences.

Identification of a new circulating recombinant form of HIV type 1, CRF11-cpx, involving subtypes A, G, J, and CRF01-AE, in Central Africa.

In this study, we characterized three full-length genome sequences with a similar mosaic structure from epidemiologically unlinked individuals from Cameroon (97CM-MP818) and the Central African Republic (99CF-MP1298 and 99CF-MP1307). Phylogenetic and recombinant analysis confirmed that the three strains had a similar complex recombinant genome, which we can designate now as CRF11-cpx. This new CRF was composed of successive fragments of subtype A, G, J, and CRF01-AE. The previously reported GR17 virus from a Greek patient infected in the Democratic Republic of Congo (DRC) has a similar structure and should be considered as the prototype strain of CRF11-cpx. This new CRF circulates in Cameroon, Central African Republic, Gabon, and DRC, although the exact prevalences remain to be determined.